U.S. patent application number 12/138879 was filed with the patent office on 2009-07-23 for sulphoximine-substituted quinazoline derivatives as immuno-modulators, their preparation and use as medicaments.
Invention is credited to Michael Haerter, Anne Mengel, Duy NGUYEN, Martina Schaefer, Hartmut Schirok, Oliver von Ahsen, Arne von Bonin.
Application Number | 20090186911 12/138879 |
Document ID | / |
Family ID | 39735498 |
Filed Date | 2009-07-23 |
United States Patent
Application |
20090186911 |
Kind Code |
A1 |
NGUYEN; Duy ; et
al. |
July 23, 2009 |
SULPHOXIMINE-SUBSTITUTED QUINAZOLINE DERIVATIVES AS
IMMUNO-MODULATORS, THEIR PREPARATION AND USE AS MEDICAMENTS
Abstract
The present invention relates to sulphoximine-substituted
quinazoline derivatives of the formula (I), processes for their
preparation and their use as a medicament for the treatment of
various diseases. ##STR00001##
Inventors: |
NGUYEN; Duy; (Berlin,
DE) ; von Bonin; Arne; (Glienicken/Nordbahn, DE)
; Haerter; Michael; (Leverkusen, DE) ; Schirok;
Hartmut; (Wuppertal, DE) ; Mengel; Anne;
(Berlin, DE) ; Schaefer; Martina; (Berlin, DE)
; von Ahsen; Oliver; (Berlin, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
39735498 |
Appl. No.: |
12/138879 |
Filed: |
June 13, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61039621 |
Mar 26, 2008 |
|
|
|
Current U.S.
Class: |
514/266.21 ;
514/266.23; 514/266.4; 544/284; 544/293 |
Current CPC
Class: |
A61P 17/04 20180101;
A61P 27/16 20180101; A61P 29/00 20180101; C07D 417/12 20130101;
A61P 19/02 20180101; A61P 1/16 20180101; A61P 7/10 20180101; A61P
11/02 20180101; C07D 401/12 20130101; A61P 7/06 20180101; A61P
13/12 20180101; A61P 17/14 20180101; A61P 25/00 20180101; A61P
27/14 20180101; A61P 35/02 20180101; C07D 239/94 20130101; A61P
15/00 20180101; A61P 5/14 20180101; A61P 7/02 20180101; A61P 11/16
20180101; A61P 25/28 20180101; C07D 413/12 20130101; A61P 7/04
20180101; A61P 21/00 20180101; A61P 11/06 20180101; A61P 37/06
20180101; A61P 17/06 20180101; A61P 37/00 20180101; A61P 37/08
20180101; A61P 17/02 20180101; A61P 43/00 20180101; A61P 5/38
20180101; A61P 11/08 20180101; A61P 9/14 20180101; A61P 35/00
20180101; C07D 403/12 20130101; A61P 17/00 20180101; A61P 19/04
20180101; A61P 1/04 20180101; A61P 3/10 20180101; C07C 381/10
20130101; A61P 27/02 20180101; A61P 11/00 20180101 |
Class at
Publication: |
514/266.21 ;
544/293; 544/284; 514/266.4; 514/266.23 |
International
Class: |
A61K 31/517 20060101
A61K031/517; C07D 239/94 20060101 C07D239/94; C07D 403/12 20060101
C07D403/12; C07D 417/12 20060101 C07D417/12; C07D 401/12 20060101
C07D401/12; C07D 413/12 20060101 C07D413/12; A61P 29/00 20060101
A61P029/00; A61P 37/00 20060101 A61P037/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 17, 2008 |
EP |
08075043.3 |
Claims
1. Compounds of the general formula (I) ##STR00150## in which
R.sup.1 represents (i) an aryl or heteroaryl ring optionally
identically or differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8, --NR.sup.6--C(O)--R.sup.11,
--NR.sup.6--C(O)--OR.sup.11, --NR.sup.6--C(O)--NR.sup.7R.sup.8,
--NR.sup.7--SO.sub.2--R.sup.11, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms, or (ii) a
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or
C.sub.2-C.sub.6-alkynyl radical optionally identically or
differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8--NR.sup.6--C(O)R.sup.11,
--NR.sup.6--C(O)--OR.sup.11, --NR.sup.6--C(O)--NR.sup.7R.sup.8,
--NR.sup.6--SO.sub.2--R.sup.11, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl, or (iii) a C.sub.3-C.sub.8 cycloalkyl or heterocyclyl
ring having 3 to 8 ring atoms and optionally identically or
differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8, --NR.sup.6--C(O)--R.sup.11,
--NR.sup.6--C(O)--OR.sup.11, --NR.sup.6--C(O)--NR.sup.7R.sup.8,
--NR.sup.6--SO.sub.2--R.sup.11, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms, R.sup.2 represents (i)
hydrogen, (ii) hydroxyl, halogen, cyano, nitro, --CF.sub.3,
--OCF.sub.3, --C(O)OR.sup.11, --C(O)OH, --C(O)NR.sup.7R.sup.8,
--C(S)NR.sup.7R.sup.8, --NR.sup.7R.sup.8, --NR.sup.6C(O)--R.sup.11,
--NR.sup.6--C(O)--OR.sup.11, --NR.sup.6--C(O)--NR.sup.7R.sup.8,
--NR.sup.6--SO.sub.2--R, or (iii) a C.sub.1-C.sub.6-alkyl or
C.sub.1-C.sub.6-alkoxy radical optionally identically or
differently mono- or polysubstituted by halogen, hydroxyl,
C.sub.1-C.sub.6-alkoxy, --CF.sub.3, --OCF.sub.3 or
--NR.sup.7R.sup.8, or (iv) a C.sub.3-C.sub.8-cycloalkyl ring
optionally identically or differently mono- or polysubstituted by
halogen, hydroxyl, C.sub.1-C.sub.6-alkoxy, --CF.sub.3, --OCF.sub.3,
--NR.sup.7R.sup.8 and/or C.sub.1-C.sub.6-alkyl, R.sup.3 represents
a C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or
C.sub.2-C.sub.6-alkynyl radical, a C.sub.3-C.sub.7-cycloalkyl or
aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a
monocyclic heteroaryl ring, in each case optionally itself
identically or differently mono- or polysubstituted by hydroxyl,
--C(O)OR.sup.11, --C(O)NR.sup.7R.sup.8, --NR.sup.7R.sup.8, cyano,
halogen, --CF.sub.3, C.sub.1-C.sub.6-alkoxy, --OCF.sub.3 and/or
C.sub.1-C.sub.6-alkyl, R.sup.4 represents hydrogen,
--SO.sub.2R.sup.11, --C(O)R.sup.11, --C(O)OR.sup.11,
--C(O)NR.sup.7R.sup.8, --C(S)OR.sup.11, --C(S)NR.sup.7R.sup.8 or
--R.sup.11, X, Y independently of one another represents --O-- or
the group --NR.sup.5--, A represents (i) a bond or (ii) an aryl or
heteroaryl ring, optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.7R.sup.8,
--NR.sup.6--C(O)--R.sup.11, --C(O)NR.sup.7R.sup.8,
--NR.sup.6--C(O)--OR.sup.11, --NR.sup.6--C(O)--NR.sup.7R.sup.8,
--NR.sup.6--SO.sub.2--R.sup.11, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms, n represents 1-6, R.sup.5
represents (i) hydrogen, (ii) a C.sub.1-C.sub.6-alkyl radical,
C.sub.3-C.sub.8-cycloalkyl or aryl ring, a heterocyclyl ring having
3 to 8 ring atoms or a heteroaryl ring, or (iii)
--C(O)--(C.sub.1-C.sub.6)-alkyl, --C(O)-phenyl, or --C(O)-benzyl,
where (ii) and (iii) are optionally identically or differently
mono- or polysubstituted by hydroxyl, --NR.sup.9R.sup.10, cyano,
halogen, --CF.sub.3, C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3, or,
if X represents --NR.sup.5--, alternatively X, R.sup.1 and R.sup.5
together form a 3- to 8-membered ring, which optionally, in
addition to the nitrogen atom, contains one or more further
heteroatoms, is optionally identically or differently mono- or
polysubstituted by hydroxyl, C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkoxy, --C(O)R.sup.11, --SO.sub.2R.sup.11, halogen
or the group --NR.sup.8R.sup.9, optionally contains 1 to 3 double
bonds and/or is optionally interrupted by one or more --C(O)--
groups, R.sup.6 represents hydrogen or a C.sub.1-C.sub.6-alkyl
radical, R.sup.7 and R.sup.8 independently of one another represent
(i) hydrogen and/or (ii) a C.sub.1-C.sub.6-alkyl radical,
C.sub.2-C.sub.6-alkenyl, C.sub.3-C.sub.8-cycloalkyl and/or aryl
ring, a heterocyclyl ring having 3 to 8 ring atoms and/or a
heteroaryl ring, are optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.9R.sup.10, cyano, halogen,
--CF.sub.3, C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3, or R.sup.7
and R.sup.8 together with the nitrogen atom form a 5- to 7-membered
ring, which optionally in addition to the nitrogen atom contains 1
or 2 further heteroatoms and which can be identically or
differently mono- or polysubstituted by hydroxyl,
--NR.sup.9R.sup.10, cyano, halogen, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3,
R.sup.9 and R.sup.10 independently of one another represent
hydrogen or a C.sub.1-C.sub.6-alkyl radical, which is optionally
identically or differently mono- or polysubstituted by hydroxyl,
R.sup.11 represents a C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl or C.sub.2-C.sub.6-alkynyl radical, a
C.sub.3-C.sub.8-cycloalkyl or aryl ring, a heterocyclyl ring having
3 to 8 ring atoms or a heteroaryl ring, in each case optionally
itself identically or differently mono- or polysubstituted by
hydroxyl, halogen, cyano, nitro, --NR.sup.7R.sup.8,
C.sub.1-C.sub.6-alkyl, --CF.sub.3, C.sub.1-C.sub.6-alkoxy and/or
--OCF.sub.3, and their salts, diastereomers and enantiomers.
2. Compounds of the general formula (I) according to claim 1, in
which R.sup.1 represents (i) an aryl or heteroaryl ring optionally
identically or differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8, cyano, halogen, C.sub.1-C.sub.6-alkoxy,
--NR.sup.6--C(O)R.sup.11, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, or (ii) a C.sub.1-C.sub.6-alkyl radical
optionally identically or differently mono- or polysubstituted by
hydroxyl, --NR.sup.7R.sup.8, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --NR.sup.6--C(O)R.sup.11, --OCF.sub.3,
--CF.sub.3, C.sub.1-C.sub.6-alkyl, or (iii) a C.sub.3-C.sub.8
cycloalkyl or heterocyclyl ring having 3 to 8 ring atoms and
optionally identically or differently mono- or polysubstituted by
hydroxyl, --NR.sup.7R.sup.8, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, R.sup.2 represents hydrogen, halogen, cyano,
--C(O)O.sup.R.sup.11, --C(O)OH, --C(O)NR.sup.7R.sup.8or a
C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.6-alkoxy radical optionally
identically or differently mono- or polysubstituted by halogen,
hydroxyl, C.sub.1-C.sub.6-alkoxy, --CF.sub.3, --OCF.sub.3 or
--NR.sup.7R.sup.8, R.sup.3 represents a C.sub.1-C.sub.6-alkyl
radical or a C.sub.3-C.sub.7-cycloalkyl ring, optionally itself
identically or differently mono- or polysubstituted by hydroxyl,
--C(O)OR.sup.11, --C(O)NR.sup.7R.sup.8, --NR.sup.7R.sup.8, cyano,
halogen, --CF.sub.3, C.sub.1-C.sub.6-alkoxy, --OCF.sub.3 and/or
C.sub.1-C.sub.6-alkyl, R.sup.4 represents hydrogen,
--SO.sub.2R.sup.11, --C(O)OR.sup.11, --C(O)NR.sup.7R.sup.8, X
represents the group --NR.sup.5--, Y represents --O--, NR.sup.5, A
represents (i) a bond or (ii) an aryl or heteroaryl ring optionally
identically or differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8, --C(O)NR.sup.7R.sup.8, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms, n represents 1-5, R.sup.5
represents hydrogen, a C.sub.1-C.sub.6-alkyl radical, a
C.sub.3-C.sub.8-cycloalkyl ring or --C(O)--(C.sub.1-C.sub.6)-alkyl,
are in each case optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.9R.sup.10, cyano, halogen,
--CF.sub.3, C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3, R.sup.7 and
R.sup.8 independently of one another represent (i) hydrogen and/or
(ii) a C.sub.1-C.sub.6-alkyl radical, a C.sub.3-C.sub.8-cycloalkyl
and/or aryl ring, a heterocyclyl ring having 3 to 8 ring atoms
and/or a heteroaryl ring, are optionally identically or differently
mono- or polysubstituted by hydroxyl, --NR.sup.9R.sup.10, cyano,
halogen, --CF.sub.3, C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3,
R.sup.11 represents a C.sub.1-C.sub.3-alkyl, a
C.sub.3-C.sub.8-cycloalkyl or aryl ring, a heterocyclyl ring having
3 to 8 ring atoms or a heteroaryl ring, in each case optionally
itself identically or differently mono- or polysubstituted by
hydroxyl, halogen, cyano, nitro, --NR.sup.7R.sup.8,
C.sub.1-C.sub.6-alkyl, --CF.sub.3, C.sub.1-C.sub.6-alkoxy and/or
--OCF.sub.3, and their salts, diastereomers and enantiomers.
3. Compounds of the general formula (I) according to claim 1, in
which R.sup.1 represents (i) a phenyl or monocyclic heteroaryl ring
optionally identically or differently mono- or polysubstituted by
hydroxyl, --NR.sup.6--C(O)--R.sup.11, cyano, C.sub.1-C.sub.6-alkyl,
or (ii) a C.sub.1-C.sub.6-alkyl radical optionally identically or
differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8, C.sub.1-C.sub.6-alkoxy and/or
C.sub.3-C.sub.6-cycloalkyl, or (iii) a C.sub.3-C.sub.8 cycloalkyl
ring, and their salts, diastereomers and enantiomers.
4. Compounds of the general formula (I) according to claim 1, in
which R.sup.2 represents hydrogen, halogen, cyano, --C(O)OR.sup.11,
--C(O)OH or a C.sub.1-C.sub.6-alkoxy radical, and their salts,
diastereomers and enantiomers.
5. Compounds of the general formula (I) according to claim 1, in
which R.sup.3 represents a C.sub.1-C.sub.3-alkyl radical, and their
salts, diastereomers and enantiomers.
6. Compounds of the general formula (I) according to claim 1, in
which R.sup.4 represents hydrogen, --SO.sub.2R.sup.11 or
--C(O)O.sup.R.sup.11, and their salts, diastereomers and
enantiomers.
7. Compounds of the general formula (I) according to claim 1, in
which R.sup.4 represents hydrogen, and their salts, diastereomers
and enantiomers.
8. Compounds of the general formula (I) according to claim 1, in
which A represents a bond or a phenyl or monocyclic heteroaryl
ring, and their salts, diastereomers and enantiomers.
9. Compounds of the general formula (I) according to claim 1, in
which X represents --NH--, and their salts, diastereomers and
enantiomers.
10. Compounds of the general formula (I) according to claim 1, in
which Y represents --O--, or --NH-- and their salts, diastereomers
and enantiomers.
11. Compounds of the general formula (I) according to claim 1, in
which R.sup.7 and R.sup.8 independently of one another represent a
C.sub.1-C.sub.6-alkyl radical, and their salts, diastereomers and
enantiomers.
12. Compounds of the general formula (I) according to claim 1, in
which n represents 1-4, and their salts, diastereomers and
enantiomers.
13. Compounds according to claim 1 of the general formula (I) in
which R.sup.1 represents (i) a phenyl or monocyclic heteroaryl ring
optionally identically or differently mono- or polysubstituted by
hydroxyl, --NR.sup.6--C(O)--R.sup.11, cyano, C.sub.1-C.sub.6-alkyl,
or (ii) a C.sub.1-C.sub.6-alkyl radical optionally identically or
differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8, C.sub.1-C.sub.6-alkoxy and/or
C.sub.3-C.sub.6-cycloalkyl, or (iii) a C.sub.3-C.sub.8 cycloalkyl
ring, R.sup.2 represents hydrogen, halogen, cyano, --C(O)OR.sup.11,
--C(O)OH, or a C.sub.1-C.sub.6-alkoxy radical, R.sup.3 represents a
C.sub.1-C.sub.6-alkyl radical R.sup.4 represents hydrogen,
--SO.sub.2R.sup.11 or --C(O)OR.sup.11, X represents --NH--, Y
represents --O-- or --NH--, A represents a bond or a phenyl or
monocyclic heteroaryl ring, n represents 1-4, R.sup.6 represents
hydrogen, R.sup.7 and R.sup.8 represent a C.sub.1-C.sub.6-alkyl
radical, R.sup.11 represents a C.sub.1-C.sub.6-alkyl radical or
phenyl ring, in each case optionally itself substituted by nitro,
and their salts, diastereomers and enantiomers.
14. Process for the preparation of the compounds according to claim
1, comprising the step which ##STR00151## reacts intermediates
according to formula (II) with compounds R.sup.1--XH, where
R.sup.1, R.sup.2, R.sup.3 and X, Y, A and n have the meanings
indicated in the general formula (I) according to claim 1 and
R.sup.4 is unequal to hydrogen.
15. Process for the preparation of the compounds according to claim
1, comprising the step which ##STR00152## reacts quinazolines of
the formula (VII) with intermediates of the formula (IV), where
R.sup.1, R.sup.2, R.sup.3 and X, Y, A and n have the meanings
indicated in the general formula (I) according to claim 1 and
R.sup.4 is unequal to hydrogen.
16. Process for the preparation of the compounds according to claim
1, comprising the steps a) imination of intermediates of the
formula (VIII) on the sulphur centre and subsequently b) oxidation
to the sulphoximine ##STR00153## where R.sup.1, R.sup.2, R.sup.3
and X, Y, A and n have the meanings indicated in the general
formula (I) according to claim 1 and R.sup.4 is unequal to
hydrogen.
17. Process according to claim 14 for the preparation of compounds
with R.sup.4 equal to hydrogen, characterized by subsequent removal
of R.sup.4 unequal to hydrogen.
18. Process for the preparation of the compounds according to claim
1, comprising the steps a) oxidation of intermediates of the
formula (VIII) to the corresponding sulphoxide and subsequently b)
sulphoximine formation ##STR00154## where R.sup.1, R.sup.2, R.sup.3
R.sup.4 and X, Y, A and n have the meanings indicated in the
general formula (I) according to claim 1.
19. Intermediates of the formula (II): ##STR00155## where R.sup.2,
R.sup.3 and Y, A and n have the meanings indicated in the general
formula (I) according to claim 1 and R.sup.4 is unequal to
hydrogen.
20. Intermediates of the formula (IV): ##STR00156## where R.sup.4
is unequal to hydrogen, R.sup.3, A and n have the meanings
indicated in the general formula (I) according to claim 1 and LG is
halogen or a mesylate, tosylate or triflate group.
21. Compounds according to claim 1 for use as medicaments.
22. Use of a compound according to claim 1 for the production of a
medicament for the treatment of diseases which involve
inflammatory, allergic and/or proliferative processes.
23. Pharmaceutical formulation comprising a compound according to
claim 1.
Description
[0001] This application claims the benefit of the filing date of
U.S. Provisional Application Ser. No. 61/039,621 filed Mar. 26
2008.
[0002] The present invention relates to sulphoximine-substituted
quinazoline derivatives, processes for their preparation, and their
use as a medicament for the treatment of various diseases.
BIOLOGICAL BACKGROUND
[0003] An over-reacting immune system is co-responsible for
numerous chronic inflammatory diseases, such as, for example,
rheumatoid arthritis, Crohn's disease, asthma and multiple
sclerosis. Owing to an increased release of proinflammatory
cytokines, damage to endogenous tissue structures results. The
interplay of the innate and adaptive immune system is of central
importance in this context (Akira et al., 2001). Modulation of the
immune system by substances which interfere with the activation of
cells of the innate and/or of the adaptive immune system has an
anti-inflammatory action and can thus attenuate the pathological
phenotype in the diseases mentioned by way of example above.
[0004] Innate immunity is based on the fact that microorganisms
such as bacteria and viruses have certain inherent features by
means of which they are recognized by the immune system and
subsequently activate. Certain pathogen-associated molecular
patterns (PAMPs) are recognized. PAMPs are recognized by the
pattern recognition receptors (PRR), which also include toll-like
receptors (TLR) (Janeway and Medzhitov, 2002). TLRs are homologues
of the Drosophila receptor protein toll. Humans have ten different
TLRs. TLR one and six are co-receptors for TLR2. TLR2 recognizes,
inter alia, lipoproteins and lipopeptides. TLR3 recognizes
double-stranded RNA. TLR4 recognizes, inter alia, LPS of
gram-negative bacteria and lipoteichoic acid of gram-positive
bacteria. TLR5 recognizes flagellin. TLR9 recognizes CpG motifs in
bacterial DANN (O'Neill, 2006). Co-receptors can further modify the
recognition capabilities of TLRs (Jiang et al., 2005).
[0005] IL-1/-18, TLR Signal Transduction
[0006] TLRs are related to IL-1/IL-18 cytokine receptors in signal
transmission. IL-1 ("endogenous pyrogen") strongly stimulates
inflammation and induces fever. Members of the IL-1R/TLR
superfamily have a TIR domain (toll/IL1 receptor). The TIR domain
is approximately 200 amino acids long and contains three conserved
sequence motifs. Proteins bearing TIR domains bind by means of a
protein-protein interaction (O'Neill et al., 2005). The subclass
one (IL-1R family) contains three Ig-like domains; the receptor is
a heterodimer. These include the IL-1 receptors one and two, the
co-receptor IL-1RAcP and the corresponding proteins of the IL-18
system. The subclass two (TLR family) contains leucine-rich motifs.
Toll-like receptors form homo- or heterodimers.
[0007] After activation of the TLR or IL-1, -18 receptors by the
appropriate ligands, a multistage signal cascade is set in motion.
The TLR or IL-1/-18 receptor complex interacts with the adaptor
protein MyD88 by means of TIR/TIR contacts. The IL-1 associated
receptor kinase (IRAK-1) normally has Tollip (toll interacting
protein) bound, which probably acts as an alleviating molecule
("silencer"). IRAK/Tollip binds to the active TLR/IL-1R complex.
MyD88 displaces Tollip whereby IRAK1 and IRAK-4 are activated, very
highly probably as a dimer by transphosphorylation. Active IRAK
leaves the receptor and binds in the cytoplasm to the adapter
molecule TRAF (Barton and Medzhitov, 2003). By means of TRAF,
further proteins are ubiquitinylated. By means of an unknown
mechanism, Ub-TRAF leads to the autophosphorylation of the S/T
kinase TAK1 (a MAP kinase kinasekinase). TAK1 phosphorylates
I.kappa.B (NF-.kappa.B activation) and MKK6. The latter is
responsible for the activation of the MAP kinases p38 and JNK.
NF-.kappa.B has been identified as a nuclear factor for the
expression of the light antibody chain kappa in B cells, but is
also involved in the regulation of many other genes. NF-.kappa.B is
retained in the cytoplasm in the inactive state, where it is bound
to the inhibitor I.kappa.B (Deng et al., 2000). Phosphorylation of
I.kappa.B causes the inhibitor I.kappa.B to be proteolytically
degraded and the transcription factor can migrate into the core.
NF-.kappa.B is a heterodimer of the subunits p65 (Rel) and p50
(Bauerle and Henkel, 1994). There are a number of members of this
family which can interact in different ways. NF-.kappa.B on its own
cannot induce transcription. For gene activation, transcriptional
co-activators are necessary, such as, for example, p300 or CBT
(Akira and Takeda, 2004).
[0008] The structures of the following patent applications form the
structurally obvious prior art:
[0009] Benzyloxy-substituted quinazoline derivatives are mentioned
in the following patent applications:. WO 2006/076246 (Inhibitors
of serine proteases), U.S. Pat. No. 5,962,458 (Inhibitors of VEGF
receptor tyrosine kinase), U.S. Pat. No. 6,593,333 (Inhibitors of
p38 kinase), U.S. Pat. No. 7,081,461 (Inhibitors of Aurora 2
kinase), WO 2004/105765 (Inhibitors of receptor tyrosine kinases),
WO 2004/94410 (Inhibitors of Aurora A and/or Aurora B kinase).
However, sulphoximine substituents for the benzyloxy radical are
not disclosed. Alkoxy-substituted quinazoline derivatives are
mentioned in the following patent applications: US 2006/0142570
(Kinase inhibitors), WO 2006/066795 (Kinase inhibitors), US
2005/101617 (ERB2 and EGFR inhibitors), WO 2005/013998 (Inhibitors
of VEGF receptor tyrosine kinase), WO 2004/046101 (ERB2 and EGFR
inhibitors), WO 2003/082831 (Inhibitors of ERB receptor tyrosine
kinase), WO 2001/077085 (Inhibitors of VEGF receptor tyrosine
kinase), WO 2000/047212 (Inhibitors of VEGF receptor tyrosine
kinase), WO 98/13354 (Inhibitors of VEGF receptor tyrosine kinase),
WO 97/30035 (Inhibitors of VEGF receptor tyrosine kinase). However,
sulphoximine substituents for the alkoxy radical are not
disclosed.
[0010] Starting from this prior art, the object of the present
invention consists in preparing further structures for therapy, in
particular for immunomodulation.
[0011] The object is achieved by sulphoximine-substituted compounds
of the general formula (I),
##STR00002##
in which [0012] R.sup.1 represents [0013] (i) a mono- or
polysubstituted aryl or heteroaryl ring optionally identically or
differently substituted by hydroxyl, --NR.sup.7R.sup.8,
--NR.sup.6--C(O)--R.sup.12, --NR.sup.6--C(O)--OR.sup.11,
--NR.sup.6--C(O)--NR.sup.7R.sup.8, --NR.sup.7--SO.sub.2--R.sup.11,
cyano, halogen, C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms, or [0014] (ii) a
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or
C.sub.2-C.sub.6-alkynyl radical optionally identically or
differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8, --NR.sup.6--C(O)R.sup.11,
--NR.sup.6--C(O)--OR.sup.11, --NR.sup.6--C(O)--NR.sup.7R.sup.8,
--NR.sup.6--SO.sub.2--R.sup.11, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms, or [0015] (iii) a
C.sub.3-C.sub.8 cycloalkyl or heterocyclyl ring having 3 to 8 ring
atoms and optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.7R.sup.8,
--NR.sup.6--C(O)--R.sup.11, --NR.sup.6--C(O)--OR.sup.11,
--NR.sup.6--C(O)--NR.sup.7R.sup.8, --NR.sup.6--SO.sub.2--R.sup.11,
cyano, halogen, C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms, [0016] R.sup.2 represents
[0017] (i) hydrogen, [0018] (ii) hydroxyl, halogen, cyano, nitro,
--CF.sub.3, --OCF.sub.3, --C(O)OR.sup.11, --C(O)OH,
--C(O)NR.sup.7R.sup.8, --C(S)NR.sup.7R.sup.8, --NR.sup.7R.sup.8,
--NR.sup.6--C(O)--R.sup.11, --NR.sup.6--C(O)--OR.sup.11,
--NR.sup.6--C(O)--NR.sup.7R.sup.8, --NR.sup.6--SO.sub.2--R.sup.11,
or [0019] (iii) a C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.6-alkoxy
radical optionally identically or differently mono- or
polysubstituted by halogen, hydroxyl, C.sub.1-C.sub.6-alkoxy,
--CF.sub.3, --OCF.sub.3 or --NR.sup.7R.sup.8, or [0020] (iv) a
C.sub.3-C.sub.8-cycloalkyl ring optionally identically or
differently mono- or polysubstituted by halogen, hydroxyl,
C.sub.1-C.sub.6-alkoxy, --CF.sub.3, --OCF.sub.3, --NR.sup.7R.sup.8
and/or C.sub.1-C.sub.6-alkyl, [0021] R.sup.3 represents [0022] a
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or
C.sub.2-C.sub.6-alkynyl radical, a C.sub.3-C.sub.7-cycloalkyl or
aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a
monocyclic heteroaryl ring, in each case itself optionally
identically or differently mono- or polysubstituted by hydroxyl,
--C(O)OR.sup.11, --C(O)NR.sup.7R.sup.8, --NR.sup.7R.sup.8, cyano,
halogen, --CF.sub.3, C.sub.1-C.sub.6-alkoxy, --OCF.sub.3 and/or
C.sub.1-C.sub.6-alkyl, [0023] R.sup.4 represents [0024] hydrogen,
--SO.sub.2R.sup.11, --C(O)R.sup.11, --C(O)OR.sup.11,
--C(O)NR.sup.7R.sup.8, --C(S)OR.sup.11, --C(S)NR.sup.7R.sup.8 or
--R.sup.11, [0025] X, Y independently of one another represents
--O-- or the group --NR.sup.5--, [0026] A represents [0027] (i) a
bond or [0028] (ii) an aryl or heteroaryl ring optionally
identically or differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8, --NR.sup.6--C(O)--R.sup.11,
--C(O)NR.sup.7R.sup.8, --NR.sup.6--C(O)--OR.sup.11,
--NR.sup.6--C(O)--NR.sup.7R.sup.8, --NR.sup.6--SO.sub.2--R.sup.11,
cyano, halogen, C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms, [0029] n represents 1-6,
[0030] R.sup.5 represents [0031] (i) hydrogen, [0032] (ii) a
C.sub.1-C.sub.6-alkyl radical, C.sub.3-C.sub.8-cycloalkyl or aryl
ring, a heterocyclyl ring having 3 to 8 ring atoms or a heteroaryl
ring, or [0033] (iii) --C(O)--(C.sub.1-C.sub.6)-alkyl,
--C(O)-phenyl, or --C(O)-benzyl, (ii) and (iii) optionally being
identically or differently mono- or polysubstituted by hydroxyl,
--NR.sup.9R.sup.10, cyano, halogen, --CF.sub.3,
C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3, [0034] or, if X
represents --NR.sup.5--, alternatively X, R.sup.1 and R.sup.5
together form a 3- to 8-membered ring which optionally, in addition
to the nitrogen atom, contains one or more further heteroatoms, is
optionally identically or differently mono- or polysubstituted by
hydroxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
--C(O)R.sup.11, --SO.sub.2R.sup.11, halogen or the group
--NR.sup.8R.sup.9, optionally contains 1 to 3 double bonds and/or
is optionally interrupted by one or more --C(O)-- groups, [0035]
R.sup.6 represents hydrogen or a C.sub.1-C.sub.6-alkyl radical,
[0036] R.sup.7 and R.sup.8 independently of one another represent
[0037] (i) hydrogen and/or [0038] (ii) a C.sub.1-C.sub.6-alkyl
radical, C.sub.2-C.sub.6-alkenyl, C.sub.3-C.sub.8-cycloalkyl and/or
aryl ring, a heterocyclyl ring having 3 to 8 ring atoms and/or a
heteroaryl ring, are optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.9R.sup.10, cyano, halogen,
--CF.sub.3, C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3, or [0039]
R.sup.7 and R.sup.8 together with the nitrogen atom form a 5- to
7-membered ring, which optionally, in addition to the nitrogen
atom, contains 1 or 2 further heteroatoms and which can be
identically or differently mono- or polysubstituted by hydroxyl,
--NR.sup.9R.sup.10, cyano, halogen, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3,
[0040] R.sup.9 and R.sup.10 independently of one another represent
hydrogen or a C.sub.1-C.sub.6-alkyl radical which is optionally
identically or differently mono- or polysubstituted by hydroxyl,
[0041] R.sup.11 represents a C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl or C.sub.2-C.sub.6-alkynyl radical, a
C.sub.3-C.sub.8-cycloalkyl or aryl ring, a heterocyclyl ring having
3 to 8 ring atoms or a heteroaryl ring, [0042] in each case
optionally itself identically or differently mono- or
polysubstituted by hydroxyl, halogen, cyano, nitro,
--NR.sup.7R.sup.8, C.sub.1-C.sub.6-alkyl , --CF.sub.3,
C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3, [0043] and their salts,
diastereomers and enantiomers.
[0044] The following definitions underlie the invention:
[0045] C.sub.n-Alkyl:
[0046] Monovalent, straight-chain or branched, saturated
hydrocarbon radical having n carbon atoms.
[0047] A C.sub.1-C.sub.6 alkyl radical comprises, inter alia, for
example:
[0048] methyl-, ethyl-, propyl-, butyl-, pentyl-, hexyl-,
iso-propyl-, iso-butyl-, sec-butyl, tert-butyl-, iso-pentyl-,
2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl,
neo-pentyl-, 1,1 -dimethylpropyl-, 4-methylpentyl-,
3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-,
1-ethylbutyl-, 3,3-dimethylbutyl-, 2,2-dimethylbutyl-,
1,1-dimethylbutyl-, 2,3-dimethylbutyl-, 1,3-dimethylbutyl-,
1,2-dimethylbutyl-.
[0049] A methyl, ethyl, propyl or isopropyl radical is
preferred.
[0050] C.sub.n-Alkenyl:
[0051] Monovalent, straight-chain or branched hydrocarbon radical
having n carbon atoms and at least one double bond.
[0052] A C.sub.2-C.sub.6 alkenyl radical comprises, inter alia, for
example:
[0053] vinyl-, allyl-, (E)-2-methylvinyl-, (Z)-2-methylvinyl-,
homoallyl-, (E)-but-2-enyl-, (Z)-but-2-enyl-, (E)-but-1-enyl-,
(Z)-but-1-enyl-, pent-4-enyl-, (E)-pent-3-enyl-, (Z)-pent-3-enyl-,
(E)-pent-2-enyl-, (Z)-pent-2-enyl-, (E)-pent-1-enyl-,
(Z)-pent-1-enyl-, hex-5-enyl-, (E)-hex-4-enyl-, (Z)-hex-4-enyl-,
(E)-hex-3-enyl-, (Z)-hex-3-enyl-, (E)-hex-2-enyl-, (Z)-hex-2-enyl-,
(E)-hex-1-enyl-, (Z)-hex-1-enyl-, isopropenyl-,
2-methylprop-2-enyl-, 1-methylprop-2-enyl-, 2-methylprop-1-enyl-,
(E)-1-methylprop-1-enyl-, (Z)-1-methylprop-1-enyl-,
3-methylbut-3-enyl-, 2-methylbut-3-enyl-, 1-methylbut-3-enyl-,
3-methylbut-2-enyl-, (E)-2-methylbut-2-enyl-,
(Z)-2-methylbut-2-enyl-, (E)-1-methylbut-2-enyl-,
(Z)-1-methylbut-2-enyl-, (E)-3-methylbut-1-enyl-,
(Z)-3-methylbut-1-enyl-, (E)-2-methylbut-1-enyl-,
(Z)-2-methylbut-1-enyl-, (E)-1-methylbut-1-enyl-,
(Z)-1-methylbut-1-enyl-, 1,1-dimethylprop-2-enyl-,
1-ethylprop-1-enyl-, 1-propylvinyl-, 1-isopropylvinyl-,
4-methylpent-4-enyl-, 3-methylpent-4-enyl-, 2-methylpent-4-enyl-,
1-methylpent-4-enyl-, 4-methylpent-3-enyl-,
(E)-3-methylpent-3-enyl-, (Z)-3-methylpent-3-enyl-,
(E)-2-methylpent-3-enyl-, (Z)-2-methylpent-3-enyl-,
(E)-1-methylpent-3-enyl-, (Z)-1-methylpent-3-enyl-,
(E)-4-methylpent-2-enyl-, (Z)-4-methylpent-2-enyl-,
(E)-3-methylpent-2-enyl-, (Z)-3-methylpent-2-enyl-,
(E)-2-methylpent-2-enyl-, (Z)-2-methylpent-2-enyl-,
(E)-1-methylpent-2-enyl-, (Z)-1-methylpent-2-enyl-,
(E)-4-methylpent-1-enyl-, (Z)-4-methylpent-1-enyl-,
(E)-3-methylpent-1-enyl-, (Z)-3-methylpent-1-enyl-,
(E)-2-methylpent-1-enyl-, (Z)-2-methylpent-1-enyl-,
(E)-1-methylpent-1-enyl-, (Z)-1-methylpent-1-enyl-,
3-ethylbut-3-enyl-, 2-ethylbut-3-enyl-, 1-ethylbut-3-enyl-,
(E)-3-ethylbut-2-enyl-, (Z)-3-ethylbut-2-enyl-,
(E)-2-ethylbut-2-enyl-, (Z)-2-ethylbut-2-enyl-,
(E)-1-ethylbut-2-enyl-, (Z)-1-ethyl-but-2-enyl-,
(E)-3-ethylbut-1-enyl-, (Z)-3-ethylbut-1-enyl-, 2-ethylbut-1-enyl-,
(E)-1-ethylbut-1-enyl-, (Z)-1-ethylbut-1-enyl-,
2-propylprop-2-enyl-, 1-propylprop-2-enyl-,
2-isopropylprop-2-enyl-,
1-isopropylprop-2-enyl-,(E)-2-propylprop-1-enyl-,
(Z)-2-propylprop-1-enyl-, (E)-1-propylprop-1-enyl-,
(Z)-1-propylprop-1-enyl-, (E)-2-isopropylprop-1-enyl-,
(Z)-2-isopropylprop-1-enyl-, (E)-1-isopropylprop-1-enyl-,
(Z)-1-isopropylprop-1-enyl-, (E)-3,3-dimethylprop-1-enyl-,
(Z)-3,3-dimethylprop-1-enyl-, 1-(1,1-dimethylethyl)ethenyl.
[0054] A vinyl or allyl radical is preferred.
[0055] C.sub.n-Alkynyl:
[0056] Monovalent, straight-chain or branched hydrocarbon radical
having n carbon atoms and at least one triple bond.
[0057] A C.sub.2-C.sub.6 alkynyl radical comprises, inter alia, for
example:
[0058] ethynyl-, prop-1-ynyl-, prop-2-ynyl-, but-1-ynyl-,
but-2-ynyl-, but-3-ynyl-, pent-1-ynyl-, pent-2-ynyl-, pent-3-ynyl-,
pent-4-ynyl-, hex-1-ynyl-, hex-2-ynyl-, hex-3-ynyl-, hex-4-ynyl-,
hex-5-ynyl-, 1-methylprop-2-ynyl-, 2-methylbut-3-ynyl-,
1-methylbut-3-ynyl-, 1-methylbut-2-ynyl-, 3-methylbut-1-ynyl-,
1-ethylprop-2-ynyl-, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl,
1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl,
4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl,
3-methylpent-1-ynyl, 2-ethylbut-3-ynyl-, 1-ethylbut-3-ynyl-,
1-ethylbut-2-ynyl-, 1-propylprop-2-ynyl-, 1-isopropylprop-2-ynyl-,
2,2-dimethylbut-3-ynyl-, 1,1-dimethylbut-3-ynyl-,
1,1-di-methylbut-2-ynyl- or a 3,3-dimethylbut-1-ynyl-.
[0059] An ethynyl-, prop-1-ynyl- or prop-2-ynyl- radical is
preferred.
[0060] C.sub.n-Cycloalkyl:
[0061] Monovalent, cyclic hydrocarbon ring having n carbon
atoms.
[0062] C.sub.3-C.sub.7-Cycloalkyl ring comprises:
[0063] cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
[0064] A cyclopropyl, cyclobutyl, cyclopentyl or a cyclohexyl ring
is preferred.
[0065] C.sub.n-Alkoxy:
[0066] Straight-chain or branched C.sub.n-alkyl ether radical of
the formula --OR with R=alkyl.
[0067] Aryl
[0068] Aryl is a monovalent, aromatic ring system without a
heteroatom.
[0069] C.sub.6-aryl is equal to phenyl. C.sub.10-aryl ist equal to
naphthyl.
[0070] Unless stated otherwise, aryl comprises only phenyl and
napthyl.
[0071] Phenyl is preferred.
[0072] Heteroatoms
[0073] Heteroatoms are to be understood as meaning oxygen, nitrogen
or sulphur atoms.
[0074] Heteroaryl
[0075] Heteroaryl is a monovalent, aromatic ring system having at
least one heteroatom different from a carbon. Heteroatoms which can
occur are nitrogen atoms, oxygen atoms and/or sulphur atoms. The
bond valency can be on any desired aromatic carbon atom or on a
nitrogen atom.
[0076] Unless stated otherwise, heteroaryl comprises only
monocyclic and bicyclic rings.
[0077] A monocyclic heteroaryl ring according to the present
invention has 5 or 6 ring atoms.
[0078] Heteroaryl rings having 5 ring atoms comprise, for example,
the rings:
[0079] thienyl, thiazolyl, furanyl, pyrrolyl, oxazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
tetrazolyl and thiadiazolyl.
[0080] Heteroaryl rings having 6 ring atoms comprise, for example,
the rings:
[0081] pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and
triazinyl.
[0082] A bicyclic heteroaryl ring according to the present
invention has 9 or 10 ring atoms.
[0083] Heteroaryl rings having 9 ring atoms comprise, for example,
the rings:
[0084] phthalidyl, thiophthalidyl, indolyl, isoindolyl, indazolyl,
benzothiazolyl, indolonyl, isoindolonyl, benzofuranyl,
benzothienyl, benzimidazolyl, benzoxazolyl, azocinyl, indolizinyl,
purinyl.
[0085] Heteroaryl rings having 10 ring atoms comprise, for example,
the rings: isoquinolinyl-, quinolinyl-, benzoxazinonyl-,
phthalazinonyl, quinolonyl-, isoquinolon-yl-, quinazolinyl-,
quinoxalinyl-, cinnolinyl-, phthalazinyl-, 1,7- or
1,8-naphthyridinyl-, quinolinyl-, isoquinolinyl-, quinazolinyl- or
quinoxalinyl-.
[0086] Monocyclic heteroaryl rings having 5 or 6 ring atoms are
preferred.
[0087] Heterocyclyl
[0088] Heterocyclyl within the meaning of the invention is a
completely hydrogenated heteroaryl (completely hydrogenated
heteroaryl=saturated heterocyclyl), i.e. a non-aromatic ring system
having at least one heteroatom different from a carbon.
[0089] Heteroatoms which can occur are nitrogen atoms, oxygen atoms
and/or sulphur atoms. The bond valency can be on any desired carbon
atom or on a nitrogen atom.
[0090] Heterocyclyl ring having 3 ring atoms comprises, for
example:
[0091] aziridinyl.
[0092] Heterocyclyl ring having 4 ring atoms comprises, for
example:
[0093] azetidinyl, oxetanyl.
[0094] Heterocyclyl rings having 5 ring atoms comprise, for
example, the rings:
[0095] pyrrolidinyl, imidazolidinyl, pyrazolidinyl and
tetrahydrofuranyl.
[0096] Heterocyclyl rings having 6 ring atoms comprise, for
example, the rings:
[0097] piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl and
thiomorpholinyl
[0098] Heterocyclyl ring having 7 ring atoms comprises, for
example:
[0099] azepanyl, oxepanyl, [1,3]-diazepanyl, [1,4]-diazepanyl.
[0100] Heterocyclyl ring having 8 ring atoms comprises, for
example:
[0101] oxocanyl, azocanyl
[0102] Unless stated otherwise, heterocyclyl denotes a heterocyclyl
ring having 3 to 8 ring atoms.
[0103] Halogen
[0104] The designation halogen comprises fluorine, chlorine,
bromine and iodine.
[0105] Compounds of the general formula (I) form a preferred
subgroup, in which [0106] R.sup.1 represents [0107] (i) an aryl or
heteroaryl ring optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.7R.sup.8, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --NR.sup.6--C(O)R.sup.11, --OCF.sub.3,
--CF.sub.3, C.sub.1-C.sub.6-alkyl, or [0108] (ii) a
C.sub.1-C.sub.6-alkyl radical optionally identically or differently
mono- or polysubstituted by hydroxyl, --NR.sup.7R.sup.8, cyano,
halogen, C.sub.1-C.sub.6-alkoxy, --NR.sup.6--C(O)R.sup.11,
--OCF.sub.3, --CF.sub.3, C.sub.1-C.sub.6-alkyl, or [0109] (iii) a
C.sub.3-C.sub.8 cycloalkyl or heterocyclyl ring having 3 to 8 ring
atoms and optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.7R.sup.8, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, [0110] R.sup.2 represents hydrogen, halogen,
cyano, --C(O)OR.sup.11, --C(O)OH, --C(O)NR.sup.7R.sup.8or a
C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.6-alkoxy radical optionally
identically or differently mono- or polysubstituted by halogen,
hydroxyl, C.sub.1-C.sub.6-alkoxy, --CF.sub.3, --OCF.sub.3 or
--NR.sup.7R.sup.8 [0111] R.sup.3 represents a C.sub.1-C.sub.6-alkyl
radical or a C.sub.3-C.sub.7-cycloalkyl ring, optionally itself
identically or differently mono- or polysubstituted by hydroxyl,
--C(O)OR.sup.11, --C(O)NR.sup.7R.sup.8, --NR.sup.7R.sup.8, cyano,
halogen, --CF.sub.3, C.sub.1-C.sub.6-alkoxy, --OCF.sub.3 and/or
C.sub.1-C.sub.6-alkyl, [0112] R.sup.4 represents [0113] hydrogen,
--SO.sub.2R.sup.11, --C(O)OR.sup.11, --C(O)NR.sup.7R.sup.8, [0114]
X represents the group --NR.sup.5--, [0115] Y represents --O-- or
the group NR.sup.5, [0116] A represents [0117] (i) a bond or [0118]
(ii) an aryl or heteroaryl ring optionally identically or
differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8, --C(O)NR.sup.7R.sup.8, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms, [0119] n represents 1-5,
[0120] R.sup.5 represents hydrogen, a C.sub.1-C.sub.6-alkyl
radical, a C.sub.3-C.sub.8-cycloalkyl ring or
--C(O)--(C.sub.1-C.sub.6)-alkyl, are in each case optionally
identically or differently mono- or polysubstituted by hydroxyl,
--NR.sup.9R.sup.10, cyano, halogen, --CF.sub.3,
C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3, [0121] R.sup.7 and
R.sup.8 independently of one another represent [0122] (i) hydrogen
and/or [0123] (ii) a C.sub.1-C.sub.6-alkyl radical, a
C.sub.3-C.sub.8-cycloalkyl and/or aryl ring, a heterocyclyl ring
having 3 to 8 ring atoms and/or a heteroaryl ring, are optionally
identically or differently mono- or polysubstituted by hydroxyl,
--NR.sup.9R.sup.10, cyano, halogen, --CF.sub.3,
C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3, [0124] R.sup.11
represents a C.sub.1-C.sub.3-alkyl, a C.sub.3-C.sub.8-cycloalkyl or
aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a
heteroaryl ring, in each case optionally itself identically or
differently mono- or polysubstituted by hydroxyl, halogen, cyano,
nitro, --NR.sup.7R.sup.8, C.sub.1-C.sub.6-alkyl , --CF.sub.3,
C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3, [0125] and their salts,
diastereomers and enantiomers.
[0126] Compounds of the general formula (I) form a particularly
preferred subgroup, in which [0127] R.sup.1 represents an aryl or
heteroaryl ring optionally substituted by hydroxyl, or [0128]
represents a C.sub.1-C.sub.6-alkyl radical or C.sub.3-C.sub.8
cycloalkyl ring optionally identically or differently mono- or
polysubstituted by --NR.sup.7R.sup.8 or C.sub.1-C.sub.6-alkoxy
[0129] R.sup.2 represents hydrogen, halogen, --C(O)OR.sup.11,
--C(O)OH or a C.sub.1-C.sub.6-alkoxy radical, [0130] R.sup.3
represents a C.sub.1-C.sub.3-alkyl radical [0131] R.sup.4
represents hydrogen, --SO.sub.2R.sup.11 or --C(O)OR.sup.11, [0132]
X represents --NH--, [0133] Y represents --O--, [0134] A represents
a bond or an aryl ring, [0135] n represents 1-4, [0136] R.sup.7 and
R.sup.8 independently of one another represent a
C.sub.1-C.sub.6-alkyl radical [0137] R.sup.11 represents a
C.sub.1-C.sub.3-alkyl radical or an aryl ring, in each case
optionally itself substituted by nitro, [0138] and their salts,
diastereomers and enantiomers.
[0139] Compounds of the general formula (I) form a likewise
particularly preferred subgroup, in which [0140] R.sup.1 represents
[0141] (i) a phenyl or monocyclic heteroaryl ring optionally
identically or differently mono- or polysubstituted by hydroxyl,
--NR.sup.6--C(O)--R.sup.11, cyano, C.sub.1-C.sub.6-alkyl, or [0142]
(ii) a C.sub.1-C.sub.6-alkyl radical optionally identically or
differently mono or polysubstituted by hydroxyl, --NR.sup.7R.sup.8,
C.sub.1-C.sub.6-alkoxy and/or C.sub.3-C.sub.6-cycloalkyl, or [0143]
(iii) a C.sub.3-C.sub.8 cycloalkyl ring. [0144] R.sup.2 represents
hydrogen, halogen, cyano, --C(O)OR.sup.11, --C(O)OH, or a
C.sub.1-C.sub.6-alkoxy radical, [0145] R.sup.3 represents a
C.sub.1-C.sub.6-alkyl radical [0146] R.sup.4 represents hydrogen,
--SO.sub.2R.sup.11 or --C(O)OR.sup.11, [0147] X represents --NH--,
[0148] Y represents --O--, or --NH-- [0149] A represents a bond or
a phenyl or monocyclic heteroaryl ring, [0150] n represents 1-4,
[0151] R.sup.6 represents hydrogen, [0152] R.sup.7 and R.sup.8
represent a C.sub.1-C.sub.6-alkyl radical, [0153] R.sup.11
represents a C.sub.1-C.sub.6-alkyl radical or phenyl ring, in each
case optionally itself substituted by nitro, [0154] and their
salts, diastereomers and enantiomers.
[0155] In the general formula (I), R.sup.1 can represent [0156] (i)
an aryl or heteroaryl ring optionally identically or differently
mono- or polysubstituted by hydroxyl, --NR.sup.7R.sup.8,
--NR.sup.6--C(O)--R.sup.11, --NR.sup.6--C(O)--OR.sup.11,
--NR.sup.6--C(O)--NR.sup.7R.sup.8, --NR.sup.7--SO.sub.2--R.sup.11,
cyano, halogen, C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms, or [0157] (ii) a
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or
C.sub.2-C.sub.6-alkynyl radical, optionally identically or
differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8, --NR.sup.6--C(O)R.sup.11,
--NR.sup.6--C(O)--OR.sup.11, --NR.sup.6--C(O)--NR.sup.7R.sup.8,
--NR.sup.6--SO.sub.2--R.sup.11, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms, or [0158] (iii) a
C.sub.3-C.sub.8 cycloalkyl or heterocyclyl ring having 3 to 8 ring
atoms and optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.7R.sup.8,
--NR.sup.6--C(O)--R.sup.11, --NR.sup.6--C(O)--OR.sup.11,
--NR.sup.6--C(O)--NR.sup.7R.sup.8, --NR.sup.6--SO.sub.2--R.sup.11,
cyano, halogen, C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms.
[0159] Preferably, R.sup.1 represents [0160] (i) an aryl or
heteroaryl ring optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.7R.sup.8, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --NR.sup.6--C(O)R.sup.11, --OCF.sub.3,
--CF.sub.3, C.sub.1-C.sub.6-alkyl, or [0161] (ii) a
C.sub.1-C.sub.6-alkyl radical optionally identically or differently
mono- or polysubstituted by hydroxyl, --NR.sup.7R.sup.8, cyano,
halogen, C.sub.1-C.sub.6-alkoxy, --NR.sup.6--C(O)R.sup.11,
--OCF.sub.3, --CF.sub.3, C.sub.1-C.sub.6-alkyl, or [0162] (iii) a
C.sub.3-C.sub.8 cycloalkyl or heterocyclyl ring having 3 to 8 ring
atoms and optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.7R.sup.8, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl.
[0163] Particularly preferably, R.sup.1 represents: [0164] (i) a
phenyl or monocyclic heteroaryl ring optionally identically or
differently mono- or polysubstituted by hydroxyl,
--NR.sup.6--C(O)--R|, cyano, C.sub.1-C.sub.6-alkyl, or [0165] (ii)
a C.sub.1-C.sub.6-alkyl radical optionally identically or
differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8, C.sub.1-C.sub.6-alkoxy and/or
C.sub.3-C.sub.6-cycloalkyl, or [0166] (iii) a C.sub.3-C.sub.8
cycloalkyl ring.
[0167] Particularly preferably, R.sup.1 also represents:
[0168] an aryl or heteroaryl ring optionally substituted by
hydroxyl, or a C.sub.1-C.sub.6-alkyl radical or C.sub.3-C.sub.8
cycloalkyl ring optionally identically or differently mono- or
polysubstituted by --NR.sup.7R.sup.8 or C.sub.1-C.sub.6-alkoxy.
[0169] In the general formula (1), R.sup.2 can represent [0170] (i)
hydrogen, [0171] (ii) hydroxyl, halogen, cyano, nitro, --CF.sub.3,
--OCF.sub.3, --C(O)OR.sup.11, --C(O)OH, --C(O)NR.sup.7R.sup.8,
--C(S)NR.sup.7R.sup.8, --NR.sup.7R.sup.8,
--NR.sup.6--C(O)--R.sup.11, --NR.sup.6--C(O)--OR.sup.11,
--NR.sup.6--C(O)--NR.sup.7R.sup.8, --NR.sup.6--SO.sub.2--R.sup.11,
or [0172] (iii) a C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.6-alkoxy
radical optionally identically or differently mono- or
polysubstituted by halogen, hydroxyl, C.sub.1-C.sub.6-alkoxy,
--CF.sub.3, --OCF.sub.3 or --NR.sup.7R.sup.8, or [0173] (iv) a
C.sub.3-C.sub.8-cycloalkyl ring optionally identically or
differently mono- or polysubstituted by halogen, hydroxyl,
C.sub.1-C.sub.6-alkoxy, --CF.sub.3, --OCF.sub.3, --NR.sup.7R.sup.8
and/or C.sub.1-C.sub.6-alkyl.
[0174] Preferably, R.sup.2 represents:
[0175] hydrogen, halogen, cyano, --C(O)OR.sup.11, --C(O)OH,
--C(O)NR.sup.7R.sup.8 or a C.sub.1-C.sub.6-alkyl or
C.sub.1-C.sub.6-alkoxy radical optionally identically or
differently mono- or polysubstituted by halogen, hydroxyl,
C.sub.1-C.sub.6-alkoxy, --CF.sub.3, --OCF.sub.3 or
--NR.sup.7R.sup.8.
[0176] Particularly preferably, R.sup.2 represents:
[0177] hydrogen, halogen, cyano, --C(O)OR.sup.11, --C(O)OH or a
C.sub.1-C.sub.6-alkoxy radical.
[0178] Particularly preferably, R.sup.2 also represents
[0179] hydrogen, halogen, --C(O)OR.sup.11, --C(O)OH or a
C.sub.1-C.sub.6-alkoxy radical.
[0180] In the general formula (1), R.sup.3 can represent
[0181] a C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or
C.sub.2-C.sub.6-alkynyl radical, a C.sub.3-C.sub.7-cycloalkyl or
aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a
monocyclic heteroaryl ring, in each case optionally itself
identically or differently mono- or polysubstituted by hydroxyl,
--C(O)OR.sup.11, --C(O)NR.sup.7R.sup.8, --NR.sup.7R.sup.8, cyano,
halogen, --CF.sub.3, C.sub.1-C.sub.6-alkoxy, --OCF.sub.3 and/or
C.sub.1-C.sub.6-alkyl.
[0182] Preferably, R.sup.3 represents
[0183] a C.sub.1-C.sub.6-alkyl radical or a
C.sub.3-C.sub.7-cycloalkyl ring, optionally itself identically or
differently mono- or polysubstituted by hydroxyl, --C(O)OR.sup.11,
--C(O)NR.sup.7R.sup.8, --NR.sup.7R.sup.8, cyano, halogen,
--CF.sub.3, C.sub.1-C.sub.6-alkoxy, --OCF.sub.3 and/or
C.sub.1-C.sub.6-alkyl,
[0184] Particularly preferably, R.sup.3 represents
[0185] a C.sub.1-C.sub.3-alkyl radical
[0186] In the general formula (I) R.sup.4 can represent
[0187] hydrogen, --SO.sub.2R.sup.11, --C(O)R.sup.11,
--C(O)OR.sup.11, --C(O)NR.sup.7R.sup.8, --C(S)OR.sup.11,
--C(S)NR.sup.7R.sup.8 or --R.sup.11,
[0188] Preferably, R.sup.4 represents
[0189] hydrogen, --SO.sub.2R.sup.11, --C(O)OR.sup.11 or
--C(O)NR.sup.7R.sup.8
[0190] Particularly preferably, R.sup.4 represents:
[0191] hydrogen, --SO.sub.2R.sup.11 or --C(O)OR.sup.11
[0192] In the general formula (I), X and Y independently of one
another represent:
[0193] --O-- or the group --NR.sup.5--.
[0194] Preferably, X represents the group --NR.sup.5--.
[0195] Particularly preferably, X represents --NH--.
[0196] Preferably, Y represents --O--, or the group
--NR.sup.5--.
[0197] Particularly preferably, Y represents --O-- or --NH--.
[0198] Exceptionally preferably, Y represents --O--.
[0199] In the general formula (I), A can represent [0200] (i) a
bond or [0201] (ii) an aryl or heteroaryl ring optionally
identically or differently mono- or polysubstituted by hydroxyl,
--NR.sup.7R.sup.8, --NR.sup.6--C(O)--R.sup.11--C(O)NR.sup.7R.sup.8,
--NR.sup.6--C(O)--OR.sup.11, --NR.sup.6--C(O)--NR.sup.7R.sup.8,
--NR.sup.6--SO.sub.2--R.sup.11, cyano, halogen,
C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms.
[0202] Preferably, A represents: [0203] (i) a bond or [0204] (ii)
an aryl or heteroaryl ring optionally identically or differently
mono- or polysubstituted by hydroxyl, --NR.sup.7R.sup.8, cyano,
halogen, C.sub.1-C.sub.6-alkoxy, --OCF.sub.3, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or
heterocyclyl having 3 to 8 ring atoms,
[0205] Particularly preferably, A represents:
[0206] a bond or a phenyl or monocyclic heteroaryl ring.
[0207] Particularly preferably, A also represents:
[0208] a bond or a phenyl ring.
[0209] In the general formula (I), n can represent 1-6.
[0210] Preferably, n represents 1-5.
[0211] Particularly preferably, n represents 1-4.
[0212] In the general formula (I), R.sup.5 can represent [0213] (i)
hydrogen, [0214] (ii) a C.sub.1-C.sub.6-alkyl radical,
C.sub.3-C.sub.8-cycloalkyl or aryl ring, a heterocyclyl ring having
3 to 8 ring atoms or a heteroaryl ring, or [0215] (iii)
--C(O)--(C.sub.1-C.sub.6)-alkyl, --C(O)-phenyl, or --C(O)-benzyl,
and (ii) and (iii) are optionally identically or differently mono-
or polysubstituted by hydroxyl, --NR.sup.9R.sup.10, cyano, halogen,
--CF.sub.3, C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3, or, if X
represents --NR.sup.5--, alternatively X, R.sup.1 and R.sup.5
together form a 3- to 8-membered ring which optionally, in addition
to the nitrogen atom, contains one or more further heteroatoms, is
optionally identically or differently mono- or polysubstituted by
hydroxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
--C(O)R.sup.11, --SO.sub.2R.sup.11, halogen or the group
--NR.sup.8R.sup.9, optionally contains 1 to 3 double bonds and/or
is optionally interrupted by one or more --C(O)-- groups,
[0216] Preferably, R.sup.5 represents:
[0217] hydrogen, a C.sub.1-C.sub.6-alkyl radical, a
C.sub.3-C.sub.8-cycloalkyl ring or --C(O)--(C.sub.1-C.sub.6)-alkyl,
are in each case optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.9R.sup.10, cyano, halogen,
--CF.sub.3, C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3.
[0218] In the general formula (I), R.sup.6 can represent
[0219] hydrogen or a C.sub.1-C.sub.6-alkyl radical.
[0220] Particularly preferably, R.sup.6 represents hydrogen.
[0221] In the general formula (I), R.sup.7 and R.sup.8
independently of one another can represent [0222] (i) hydrogen
and/or [0223] (ii) a C.sub.1-C.sub.6-alkyl radical,
C.sub.2-C.sub.6-alkenyl, C.sub.3-C.sub.8-cycloalkyl and/or aryl
ring, a heterocyclyl ring having 3 to 8 ring atoms and/or a
heteroaryl ring, are optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.9R.sup.10, cyano, halogen,
--CF.sub.3, C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3, or [0224]
R.sup.7 and R.sup.8 together with the nitrogen atom form a 5- to
7-membered ring, which optionally in addition to the nitrogen atom
contains 1 or 2 further heteroatoms and which can be identically or
differently mono- or polysubstituted by hydroxyl,
--NR.sup.9R.sup.10, cyano, halogen, --CF.sub.3,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy and/or
--OCF.sub.3.
[0225] Preferably, R.sup.7 and R.sup.8 independently of one another
represent: [0226] (i) hydrogen and/or [0227] (ii) a
C.sub.1-C.sub.6-alkyl radical, a C.sub.3-C.sub.8-cycloalkyl and/or
aryl ring, a heterocyclyl ring having 3 to 8 ring atoms and/or a
heteroaryl ring, are optionally identically or differently mono- or
polysubstituted by hydroxyl, --NR.sup.9R.sup.10, cyano, halogen,
--CF.sub.3, C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3.
[0228] Particularly preferably, R.sup.7 and R.sup.8 independently
of one another represent: a C.sub.1-C.sub.6-alkyl radical.
[0229] In the general formula (I), R.sup.9 and R.sup.10
independently of one another represent:
[0230] hydrogen or a C.sub.1-C.sub.6-alkyl radical, which is
optionally identically or differently mono- or polysubstituted by
hydroxyl,
[0231] In the general formula (I), R.sup.11 can represent
[0232] for a C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or
C.sub.2-C.sub.6-alkynyl radical, a C.sub.3-C.sub.8-cycloalkyl or
aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a
heteroaryl ring, in each case optionally itself identically or
differently mono- or polysubstituted by hydroxyl, halogen, cyano,
nitro, --NR.sup.7R.sup.8, C.sub.1-C.sub.6-alkyl , --CF.sub.3,
C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3.
[0233] Preferably, R.sup.11 represents
[0234] a C.sub.1-C.sub.3-alkyl, a C.sub.3-C.sub.8-cycloalkyl or
aryl ring, a heterocyclyl ring having 3 to 8 ring atoms or a
heteroaryl ring,
[0235] in each case optionally itself identically or differently
mono- or polysubstituted by hydroxyl, halogen, cyano, nitro,
--NR.sup.7R.sup.8, C.sub.1-C.sub.6-alkyl , --CF.sub.3,
C.sub.1-C.sub.6-alkoxy and/or --OCF.sub.3.
[0236] Particularly preferably, R.sup.11 represents:
[0237] for a C.sub.1-C.sub.3-alkyl radical or a phenyl ring, in
each case optionally itself substituted by nitro.
[0238] All compounds which result by any possible combination of
the abovementioned possible, preferred and particularly preferred
meanings of the substituents are likewise to be regarded as covered
by the present invention.
[0239] Particular embodiments of the invention moreover consist in
compounds which result by combination of the meanings for the
substituents directly disclosed in the examples.
[0240] The salts of the compounds are likewise to be regarded as
covered by the present invention.
[0241] The formulation of the compounds according to the invention
to give pharmaceutical preparations is carried out in a manner
known per se, by converting the active compound or compounds into
the desired administration form using the excipients customary in
galenics.
[0242] Excipients which can be used here are, for example,
vehicles, fillers, disintegrants, binders, moisturizers,
lubricants, absorbents and adsorbents, diluents, solvents,
cosolvents, emulsifiers, solubilizers, taste corrigents,
colourants, preservatives, stabilizers, wetting agents, salts for
changing the osmotic pressure or buffers. Reference is to be made
here to Remington's Pharmaceutical Science, 15th ed. Mack
Publishing Company, East Pennsylvania (1980).
[0243] The pharmaceutical formulations can be present
[0244] in solid form, for example as tablets, coated tablets,
pills, suppositories, capsules, transdermal systems or
[0245] in semi-solid form, for example as ointments, creams, gels,
suppositories, emulsions or
[0246] in liquid form, for example as solutions, tinctures,
suspensions or emulsions.
[0247] Excipients within the meaning of the invention can be, for
example, salts, saccharides (mono-, di-, tri-, oligo-, and/or
polysaccharides), proteins, amino acids, peptides, fats, waxes,
oils, hydrocarbons and their derivatives, where the excipients can
be of natural origin or can be obtained synthetically or partially
synthetically.
[0248] Tablets, coated tablets, capsules, pills, powders, granules,
pastilles, suspensions, emulsions or solutions, in particular, are
suitable for oral or peroral administration. Suspensions, emulsions
and especially solutions, in particular, are suitable for
parenteral administration.
[0249] On account of their anti-inflammatory and in addition
immunosuppressive action, the compounds of the general formula (I)
according to the invention can be used for local and systemic
administration as medicaments for the treatment or prophylaxis of
the following disease states in mammals and humans: [0250] (i)
Pulmonary diseases which involve inflammatory, allergic and/or
proliferative processes: [0251] Chronic obstructive pulmonary
diseases of any genesis, especially bronchial asthma [0252]
Bronchitis of varying genesis [0253] Adult respiratory distress
syndrome (ARDS), acute respiratory distress syndrome [0254]
Bronchiectasis [0255] All forms of restrictive pulmonary diseases,
especially allergic alveolitis, [0256] Pulmonary oedema, in
particular allergic [0257] Sarcoidosis and granulomatosis, in
particular Boeck disease [0258] (ii) Rheumatic diseases/autoimmune
diseases/joint diseases, which involve inflammatory, allergic
and/or proliferative processes: [0259] All forms of rheumatic
diseases, in particular rheumatoid arthritis, acute rheumatic
fever, rheumatic polymyalgia, Behcet's disease [0260] Reactive
arthritis [0261] Inflammatory soft-tissue diseases of other genesis
[0262] Arthritic symptoms in degenerative joint diseases
(arthroses) [0263] Vitiligo [0264] Collagenoses of any origin, e.g.
systemic lupus erythematosus, scleroderma, polymyositis,
dermatomyositis-Sjogren's syndrome, Still's disease, Felty's
syndrome [0265] Sarcoidoses and granulomatoses [0266] Soft tissue
rheumatism [0267] (iii) Allergies or pseudoallergic diseases, which
involve inflammatory, and/or proliferative processes: [0268] All
forms of allergic reactions, e.g. Quincke's oedema, hayfever,
insect bite, allergic reactions to medicaments, blood derivatives,
contrast agents etc., anaphylactic shock, urticaria, allergic and
irritative contact dermatitis, allergic vascular diseases [0269]
Allergic vasculitis [0270] (iv) Vascular inflammation (vasculitis)
[0271] Panarteritis nodosa, temporal arteritis, nodal fever [0272]
Polyarteritis nodosa [0273] Wegener's granulomatosis [0274] Giant
cell arteritis [0275] (v) Dermatological diseases which involve
inflammatory, allergic and/or proliferative processes: [0276]
Atopic dermatitis (especially in children) [0277] All forms of
eczema such as, for example, atopic eczema (esp. in children)
[0278] Exanthema of any genesis or dermatoses [0279] Psoriasis and
parapsoriasis disorder [0280] Pityriasis rubra pilaris [0281]
Erythematous diseases caused by different noxae, e.g. rays,
chemicals, burns etc. [0282] Bullous dermatoses such as, for
example, autoimmune pemphigus vulgaris, bullous pemphigoid [0283]
Diseases of the lichenoid type, [0284] Pruritus (e.g. of allergic
genesis) [0285] Rosacea disorder [0286] Stevens-Johnson syndrome
[0287] Manifestation of vascular diseases [0288] Hair loss such as
alopecia areata [0289] Cutaneous lymphoma [0290] (vi) Renal
diseases which involve inflammatory, allergic and/or proliferative
processes: [0291] Nephrotic syndrome [0292] All nephrites, e.g.
glomerulonephritis [0293] (vii) Hepatic diseases which involve
inflammatory, allergic and/or proliferative processes: [0294] acute
hepatitis of varying origin [0295] chronic aggressive and/or
chronic intermittent hepatitis [0296] (viii) Gastrointestinal
diseases which involve inflammatory, allergic and/or proliferative
processes: [0297] regional enteritis (Crohn's disease) [0298]
ulcerative colitis [0299] gastroenteritis of varying origin, e.g.
endemic sprue [0300] (ix) Eye diseases which involve inflammatory,
allergic and/or proliferative processes: [0301] allergic keratitis,
uveitis, iritis, [0302] conjunctivitis [0303] blepharitis [0304]
optical nerve neuritis [0305] chorioiditis [0306] sympathetic
ophthalmia [0307] (x) Diseases of the otorhinolaryngological
region, which involve inflammatory, allergic and/or proliferative
processes: [0308] allergic rhinitis, hayfever [0309] external
otitis, e.g. caused by contact eczema [0310] (xi) neurological
diseases which involve inflammatory, allergic and/or proliferative
processes: [0311] cerebral oedema, especially allergic cerebral
oedema [0312] multiple sclerosis [0313] acute encephalomyelitis
[0314] meningitis, especially allergic [0315] Guillain-Barre
syndrome [0316] Alzheimer's disease [0317] (xii) Blood diseases
which involve inflammatory, allergic and/or proliferative
processes, such as, for example: Hodgkin's disease or non-Hodgkin's
lymphoma, thrombocytaemias, erythrocytoses [0318] Acquired
haemolytic anaemia [0319] Idiopathic thrombocytopenia [0320]
Idiopathic granulocytopenia [0321] (xiii) Oncoses which involve
inflammatory, allergic and/or proliferative processes [0322] Acute
lymphatic leukaemia [0323] Malignant lymphoma [0324]
Lymphogranulomatoses [0325] Lymphosarcomas [0326] (xiv) Endocrine
diseases which involve inflammatory, allergic and/or proliferative
processes such as, for example: [0327] Endocrine orbitopathy [0328]
De Quervain thyroiditis [0329] Hashimoto's thyroiditis [0330]
Basedow's disease [0331] Granulomatous thyroiditis [0332]
Lymphadenoid goitre [0333] Autoimmune adrenalitis [0334] Diabetes
mellitus, in particular type 1 diabetes [0335] Endometriosis [0336]
(xv) Organ and tissue transplants, graft-versus-host disease [0337]
(xvi) Severe states of shock, e.g. anaphylactic shock, systemic
inflammatory response syndrome (SIRS)
[0338] One subject of the invention is the use of the compounds of
the general formula (I) according to the invention for the
production of a medicament.
[0339] A further subject of the invention is the use of the
compounds according to the invention for the treatment of diseases
which involve inflammatory, allergic and/or proliferative
processes.
[0340] Preparation of the Compounds According to the Invention
[0341] Process Variant 1:
##STR00003##
[0342] According to Y. Hang et al. (Org. Lett., 2004, 6,
4775-4778), the preparation of the compounds of the general formula
(I) according to the invention is carried out by reaction of the
intermediates as in formula (II) with compounds R.sup.1--XH in the
presence of acetic acid in acetonitrile as a solvent in a
microwave, where R.sup.1, R.sup.2, R.sup.3 and X, Y, A and n have
the meanings indicated in the general formula (I) according to
claims 1 to 13. In this way, compounds with R.sup.4 unequal to
hydrogen are obtainable. By subsequent removal of R.sup.4,
compounds with R.sup.4 equal to hydrogen can be obtained.
[0343] Preparation of the Intermediates of the Formula (II):
##STR00004##
[0344] The substituents R.sup.2, R.sup.3 and Y, A and n have the
meanings indicated in the general formula (I) according to claims 1
to 13, where R.sup.4 next to R.sup.4 is unequal to hydrogen.
Intermediates of the formula (II) are obtained by a nucleophilic
substitution reaction of intermediates of the formula (III) with
intermediates of the formula (IV). Intermediates of the formula
(IV) are functionalized here using a group LG suitable for this
purpose. Halogen and a mesylate, tosylate or triflate group, for
example, are suitable as an LG. For the reaction of the
intermediates (III) with (IV), inter alia, sodium carbonate,
potassium carbonate or caesium carbonate are used as a base.
Suitable solvents are, for example, acetone or
dimethylformamide.
[0345] Preparation of the Intermediates of the Formula (III)
##STR00005##
[0346] Intermediates of the formula (III) are obtained by reaction
of intermediates of the formula (V) with N,N-dimethylformamide
dimethyl acetal, where R.sup.2 and Y have the meanings indicated in
the general formula (I) according to claims 1 to 13.
[0347] Preparation of the Intermediates of the Formula (IV)
##STR00006##
[0348] Variant IV-A
[0349] 1. Oxidation to the Sulphoxide.
[0350] A thioether of the formula (VI) is initially converted to
the corresponding sulphoxide, where A and R.sup.3 have the meanings
indicated in the general formula (I) according to claims 1 to 13.
Suitable oxidizing agents for this transformation are, for example,
sodium periodate, meta-chloroperbenzoic acid or hydrogen
peroxide.
[0351] 2. Sulphoximine Preparation
[0352] One of the most important methods of preparation of
sulphoximines is the reaction of a sulphoxide with hydrazoic acid,
which is generated in situ, for example from the reaction of sodium
azide and conc. sulphuric acid (M. Reggelin, C. Zur, Synthesis
2000, 1, 1). The reaction can be carried out in an organic solvent,
such as chloroform.
[0353] Further methods for the synthesis of sulphoximines are, for
example, the reaction of sulphoxides with
[0354] a) TsN.sub.3 ((a) R. Tanaka, K. Yamabe, J. Chem. Soc. Chem.
Commun. 1983, 329; (b) H. Kwart, A. A. Kahn, J. Am. Chem. Soc.
1967, 89, 1959)).
[0355] b) N-tosylimino phenyl iodinane and catalytic amounts of
Cu(I) triflate (J. F. K. Muller, P. Vogt, Tetrahedron Lett. 1998,
39, 4805)
[0356] c) Boc azide and catalytic amounts of iron(ll) chloride (T.
Bach, C. Korber, Tetrahedron Lett. 1998, 39, 5015) or
[0357] d) o-Mesitylenesulphonylhydroxylamine (MSH) (C. R. Johnson,
R. A. Kirchhoff, H. G. Corkins, J. Org. Chem. 1974, 39, 2458).
[0358] e)
[N-(2-(Trimethylsilyl)ethanesulphonyl)imino]phenyliodinane
(Phl=NSes) (S. Cren, T. C. Kinahan, C. L. Skinner and H. Tye,
Tetrahedron Lett. 2002, 43, 2749).
[0359] f) Trifluoroacetamide or sulphonylamides in combination with
iodobenzene diacetate, magnesium oxide and catalytic amounts of
rhodium(II) acetate dimer (H. Okamura, C. Bolm, Org. Lett. 2004, 6,
1305.
[0360] g) Sulphonylamides in combination with iodobenzene diacetate
and catalytic amounts of a chelating ligand and silver salts (G. Y.
Cho, C. Bolm, Org. Lett. 2005, 7, 4983).
[0361] h) NsNH.sub.2 and iodobenzene diacetate (G. Y. Cho, C. Bolm,
Tetrahedron Lett. 2005, 46, 8007).
[0362] i) NsNH.sub.2 and iodosylbenzene in the presence of
catalytic amounts of Fe(acac).sub.3 (O. G. Mancheno, C. Bolm, Org.
Lett. 2006, 8, 2349-2352).
[0363] 3. Protection of the Sulphoximine
[0364] If the preparation of the sulphoximine is carried out, for
example, by means of sodium azide and sulphuric acid or by means of
o-mesitylenesulphonylhydroxylamine (MSH), further derivatizations
can subsequently be performed on the nitrogen of the sulphoximine
group. For example, the sulphoximine nitrogen can be alkylated,
acylated, arylated or the reaction can be carried out using ethyl
chloroformate (for derivatization on the sulphoximine nitrogen, for
this see M. Reggelin, C. Zur, Synthesis 2000, 1,1-64. C. Bolm, J.
Sedelmeier, J. Org. Chem. 2005, 70, 6904-6906).
[0365] 4. Conversion of FG to LG
[0366] Functional groups FG are, for example, carboxylic acid and
ester. These groups can be reduced to the corresponding alcohol. In
a subsequent step, the alcohol is converted to a mesylate, tosylate
and triflate group belonging to the LG group.
[0367] If A=aryl/hetaryl and n=1, FG can be, for example, a
hydroxyl group or hydrogen optionally present in protected form. By
means of free radical halogenation, this hydrogen can be replaced
by a halogen substituent.
[0368] Variant IV-B
[0369] 1. Imination on the Sulphur
[0370] Starting from the thioether (VI), the preparation of the
corresponding sulphimides is carried out, inter alia, by means of
Fe(acac).sub.3 (O. G. Mancheno, C. Bolm, Org. Lett. 2006, 8,
2349-2352) or [Rh.sub.2(OAc).sub.4] (H. Okamura, C. Bolm, Org.
Lett. 2004, 6,1305-1307)-catalysed imination on the sulphur centre.
If the imination is chosen as the first reaction step, then this
applies initially for the imination R.sup.4 unequal to hydrogen
[0371] 2. Oxidation to the Sulphoximine
[0372] Sulphimides can be oxidized to the sulphoximine (for this
see N. Pesa, C. J. Welch, A. N. Boa J. Heterocycl. Chem. 2005,
599-607).
[0373] 3. Conversion of FG to LG
[0374] Functional groups FG are, for example, carboxylic acid and
ester. These groups can be reduced to the corresponding alcohol. In
a subsequent step, the alcohol is converted to a mesylate, tosylate
and triflate group belonging to the LG group.
[0375] If A=aryl/hetaryl and n=1, FG can be, for example, a
hydroxyl group or hydrogen optionally present in protected form. By
means of a free radical halogenation, this hydrogen can be replaced
by a halogen substituent.
[0376] The preparation of enantiomerically pure sulphoximines is
described, for example, by means of resolution using
enantiomerically pure camphor-10-sulphonic acid ((a) C. R. Johnson,
C. W. Schroeck, J. Am. Chem. Soc. 1973, 95, 7418; (b) C. S. Shiner,
A. H. Berks, J. Org. Chem. 1988, 53, 5543). A further method for
the preparation of optically active sulphoximines consists in the
stereoselective imination of optically active sulphoxides ((a) C.
Bolm, P. Muller, K. Harms, Acta Chem. Scand. 1996, 50, 305; (b) Y.
Tamura, J. Minamikawa, K. Sumoto, S. Fujii, M. Ikeda, J. Org. Chem.
1973, 38,1239; (c) (H. Okamura, C. Bolm, Org.Lett. 2004, 6,
1305).
[0377] Process Variant 2:
##STR00007##
[0378] The preparation of the compounds of the general formula (I)
according to the invention is carried out in this variant by the
reaction of the quinazolines of the formula (VII) with
intermediates of the formula (IV), where R.sup.1, R.sup.2, R.sup.3
and X, Y, A and n have the meanings indicated in the general
formula (I) according to claims 1 to 13. In this way, initially
compounds with R.sup.4 unequal to hydrogen are obtainable. In a
subsequent step, R.sup.4 can be removed with the obtainment of
compounds with R.sup.4 equal to hydrogen. The reaction is carried
out analogously to the reaction of the intermediates of the formula
(III) with intermediates of the formula (IV) (see Scheme 2).
[0379] Preparation of the Intermediates of the Formula (VII)
[0380] The synthesis of the quinazolines of the (VII) is carried
out in a manner analogous to that described in Process variant 1
(see Scheme 1) or according to other methods known to the person
skilled in the art (for this see Science of Synthesis, Houben-Weyl
Methods of Molecular Transformations, Thieme Verlag, 2004, Volume
16, pages 573-749).
[0381] Process Variant 3:
##STR00008##
[0382] In this process variant, the compounds of the general
formula (I) according to the invention can be prepared in two ways.
Starting from compounds of the formula (VIII), the sulphur centre
is converted to the sulphoxide, followed by the formation of the
corresponding sulphoximine, where R.sup.1, R.sup.2, R.sup.3,
R.sup.4and X, Y, A and n have the meanings indicated in the general
formula (I) according to claims 1 to 13. Alternatively, compounds
of the formula (VIII) can initially be converted by an imination
reaction on the sulphur centre to a sulphimide, which is
subsequently oxidized to the sulphoximine.
[0383] If the imination is chosen as the first reaction step, then
this applies initially for the imination R.sup.4 unequal to
hydrogen. After the oxidation of the sulphimide to the
corresponding sulphoximine, R.sup.4 can be removed with the
obtainment of compounds with R.sup.4 equal to hydrogen.
[0384] Preparation of the Intermediates of the Formula (VII):
[0385] Variant VIII-A
##STR00009##
[0386] Intermediates of the formula (VIII) can be prepared
analogously to Process variant 1 (see Scheme 1). Intermediates of
the formula (IX) are obtained analogously to Scheme 3 by reaction
of the intermediates of the formula (III) with intermediates of the
formula (X). R.sup.1, R.sup.2, R.sup.3 and X, Y, A and n have the
meanings indicated in the general formula (I) according to claims 1
to 13.
##STR00010##
[0387] Variant VIII-B
[0388] Alternatively and analogously to Process variant 2 (see
Scheme 5), intermediates of the formula (VIII) can be prepared by
reaction of the intermediates of the formula (VII) with
intermediates of the formula (X).
[0389] Halogen and a mesylate, tosylate or triflate group and in
this case also a hydroxyl group are suitable, for example, as
LG.
[0390] If LG is a hydroxyl group, the linkage of the intermediates
of the formula (V) with intermediates of the formula (X) can be
carried out, for example, by means of a Mitsunobu reaction (O.
Mitsunobu Synthesis 1981, 1-27).
[0391] Experimental Section:
I. SYNTHESIS
[0392] General Working Procedures (GWP)
[0393] General Working Procedure 1 (GWP 1): Preparation of
Sulphoxides
[0394] Thioether (1.0 eq) is introduced into methanol (15 ml/1 mmol
of thioether) and tetra-hydrofuran (12 ml/1 mmol). After addition
of a solution of sodium periodate (1.3 eq) in water (7 ml/l mmol of
periodate), the reaction mixture is stirred at room temperature and
added to dilute aqueous sodium chloride solution. It is extracted
with ethyl acetate. After drying the combined organic phases over
sodium sulphate and removing the solvents, the residue is purified
by means of chromatography.
[0395] General Working Procedure 2 (GWP 2): Preparation of
Sulphoximines
[0396] Sulphoxide (1.0 eq) is suspended in chloroform (1 ml/l mmol)
and treated with sodium azide (2.3 eq). Sulphuric acid (9.5 eq) is
added dropwise at 0.degree. C. and the reaction batch is
subsequently stirred at 45.degree. C. for 72 h and rendered basic
by means of 4N sodium hydroxide solution with ice bath cooling.
After removal of the solvents, the residue is purified by means of
chromatography.
[0397] General Working Procedure 3 (GWP 3): Reaction of the
Sulphoximines with Ethyl Chloroformate
[0398] A solution of sulphoximine (1.0 eq) in pyridine (10 ml/l
mmol) is treated dropwise at room temperature with ethyl
chloroformate (5.0 eq) and subsequently stirred at room
temperature. The batch is added to dilute NaCl solution and
extracted with ethyl acetate. After drying the combined organic
phases over sodium sulphate and subsequently removing the solvents,
the residue is purified by means of chromatography.
[0399] General Working Procedure 4 (GWP 4): Free Radical
Bromination
[0400] The compound prepared by means of GWP3 (1.0 eq) is
introduced into carbon tetrachloride (1 ml/1 mmol), treated with
N-bromosuccinimide (1.0 eq) and azobisisobutyronitrile (0.1 eq) and
subsequently refluxed for 5 hours. After cooling to RT,
precipitated crystals are filtered off with suction and washed with
CCl.sub.4. The filtrate is concentrated to dryness and the residue
is purified by chromatography.
[0401] General Working Procedure 5 (GWP 5): Preparation of
Compounds of the General Formula (I) According to Process Variant 1
(see Scheme 1)
[0402] According to Y. Hang et al. (Org. Lett., 2004, 6,
4775-4778), the intermediate of the formula (II) (1.0 eq) is
introduced into acetonitrile (1 mL/0.1 mmol)) and acetic acid (6.0
eq), treated with amine (1.2 eq) and irradiated with microwaves at
160.degree. C. with stirring for 10 minutes. The reaction mixture
is subsequently concentrated. The residue is treated with saturated
NaHCO.sub.3 solution. The aqueous phase is extracted with ethyl
acetate. After drying the combined organic phases over sodium
sulphate and removing the solvents, the residue is purified by
means of chromatography.
[0403] General Working Procedure 6 (GWP 6): Removal of the
Ethoxycarbonyl Group on the Sulphoximine
[0404] The compound prepared according to GWP 5 (1.0 eq) is
dissolved in ethanol (10 ml/1 mmol). After addition of sodium
ethoxide (3.6 eq), the reaction mixture is stirred at 60.degree. C.
for 6 hours and is subsequently added to dilute aqueous sodium
carbonate solution. The aqueous phase is extracted with ethyl
acetate and the combined organic phases are dried over sodium
sulphate. After removing the solvents, the residue is purified by
means of chromatography.
[0405] 1. Process Variant 1
EXAMPLE 1.1
(RS)-S-[3-({[6-Bromo-4-(isopropylamino)quinazolin-7-yl]oxy}methyl)phenyl]--
N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00011##
[0407] 1.1.a) Preparation of the Intermediates
Compound 1.1.a.1
(RS)-3-(Methylsulphinyl)toluene
##STR00012##
[0409] According to GWP 1, in the case of reaction of
3-methylthioanisole (5.0 g, 36.2 mmol) the desired product is
obtained after chromatographic purification (silica gel,
hexane/ethyl acetate: 0.fwdarw.100% ethyl acetate) in 83% yield
(4.6 g).
[0410] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 2.35 (s, 3H), 2.68
(s, 3H), 7.30-7.32 (m, 1H), 7.42-7.46 (m, 3H).
Compound 1.1.a.2
(RS)-S-Methyl-S-(m-tolyl)sulphoximide
##STR00013##
[0412] According to GWP 2, in the case of the reaction of
(RS)-3-(methylsulphinyl)toluene (4.6 g, 29.8 mmol) the desired
product is obtained after chromatographic purification (silica gel,
hexane/ethyl acetate: 0.fwdarw.100% ethyl acetate, then ethyl
acetate/methanol: 4/1) in 74% yield (3.74 g).
[0413] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 2.37 (s, 3H), 3.00
(s, 3H), 4.11 (s,1H), 7.41-7.45 (m, 2H), 7.67-7.72 (m, 2H).
Compound 1.1.a.3
(RS)-N-(Ethoxycarbonyl)-S-methyl-S-(m-tolyl)sulphoximide
##STR00014##
[0415] According to GWP 3, in the case of the reaction of
(RS)-S-methyl-S-(m-tolyl)sulphoximide (3.74 g, 22.1 mmol) the
desired product is obtained after chromatographic purification
(silica gel, hexane/ethyl acetate: 0.fwdarw.100% ethyl acetate,
then ethyl acetate/methanol: 4/1) in 99% yield (5.3 g).
[0416] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 1,05 (t, 3H), 2.39
(s, 3H), 3.40 (s, 3H), 3.82-3.91 (m, 2H), 7.52-7.54 (m, 2H),
7.71-7.74 (m, 2H).
Compound 1.1.a.4
(RS)-S-[3-(Bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00015##
[0418] According to GWP 4, in the case of the reaction of
(RS)-N-(ethoxycarbonyl)-S-methyl-S-(m-tolyl)sulphoximide (2.71 g,
11.2 mmol) the desired product is obtained after chromatographic
purification (silica gel, hexane/ethyl acetate: 0.fwdarw.100% ethyl
acetate, then ethyl acetate/methanol: 4/1) in 31% yield (1.1
g).
[0419] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1,04 (t, 3H),
3.44(s, 3H), 3.84-3.91 (m, 2H), 4.80 (s, 2H), 7.64 (t, 1H), 7.79
(d, 1H), 7.86 (d, 1H), 8.02 (s,1H).
Compound 1.1.a.5
2-Amino-5-bromo-4-methoxybenzonitrile
##STR00016##
[0421] 2-Amino-4-methoxybenzonitrile (4.47 g, 30.2 mmol) is
dissolved in 70 ml of dioxane and treated at 0.degree. C. with
bromine (1.71 ml, 33.2 mmol). It is subsequently stirred at
0.degree. C. for one hour. After addition of diethyl ether, the
resulting crystals are filtered off with suction. The desired
product is obtained in 81% yield (5.52 g).
[0422] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 3.75 (s, 3H),
6.30-6.50 (m, 3H), 7.54 (s,1H).
Compound 1.1.a.6
(E/Z)-N'-(4-Bromo-2-cyano-5-methoxyphenyl)-N,N-dimethylformimidamide
##STR00017##
[0424] 2-Amino-5-bromo-4-methoxybenzonitrile (3.0 g, 13.2 mmol) is
treated with N,N-di-methylformamide dimethyl acetal (6.5 ml, 48.9
mmol) and subsequently stirred at room temperature for 24 hours.
The reaction mixture is concentrated to dryness a number of times
with toluene. The desired product is obtained after chromatographic
purification (silica gel, hexane/ethyl acetate: 0.fwdarw.100% ethyl
acetate, then ethyl acetate/methanol: 4/1) in 42% yield (1.56
g).
[0425] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 2.95 (s, 3H), 3.05
(s, 3H), 3.87 (s, 3H), 6.80 (s, 1H), 7.75 (s, 1H), 7.99 (s,
1H).
Compound 1.1.a.7
(E/Z)-N'-(4-Bromo-2-cyano-5-hydroxyphenyl)-N,N-dimethylformimidamide
##STR00018##
[0427]
(E/Z)-N'-(4-Bromo-2-cyano-5-methoxyphenyl)-N,N-dimethylformimidamid-
e (1.28 g, 4.54 mmol) is dissolved in 45 ml of methylene chloride.
Boron tribromide solution (1 M) in methylene chloride (91 ml, 91
mmol) is added dropwise. After 20 hours at room temperature, the
reaction is terminated by addition of methanol. The reaction
mixture is concentrated to dryness a number of times with toluene.
The desired product is obtained after chromatographic purification
(silica gel, hexane/ethyl acetate: 0.fwdarw.100% ethyl acetate,
then ethyl acetate/methanol: 4/1) in 21% yield (250 mg).
[0428] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 2.92 (s, 3H), 3.02
(s, 3H), 6.50 (s, 1 H), 7.69 (s, 1H), 7.75 (s, 1H), 11.01 (br,
1H).
Compound 1.1.a.8
(E/Z)-N'-(4-Bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimi-
doyl]-benzyloxy}phenyl)-N,N-dimethylformimidamide
##STR00019##
[0430]
(E/Z)-N'-(4-Bromo-2-cyano-5-hydroxyphenyl)-N,N-dimethylformimidamid-
e (720 mg, 2.69 mmol) and
(RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-methyl-sulphoximide
(945 mg, 2.95 mmol) are suspended in 12 ml of acetone. After
addition of potassium carbonate (687 mg, 4.97 mmol), the reaction
mixture is refluxed for 6 hours. The batch is diluted with ethyl
acetate, and the organic phase is washed with water and dried over
sodium sulphate. The desired product is obtained after removing the
solvent and after chromatographic purification (silica gel,
hexane/ethyl acetate: 0.fwdarw.100% ethyl acetate, then ethyl
acetate/methanol: 4/1) in 46% yield (620 mg).
[0431] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 1.02 (t, 3H), 2.96
(s, 3H), 3.06 (s, 3H), 3.44 (s, 3H), 3.79-3.91 (m, 2H), 5.37 (s,
2H), 6.96 (s, 1H), 7.71 (t, 1H), 7.79-7.81 (m, 2H), 7.91 (d, 1H),
7.96 (s, 1H), 8.08 (s, 1H).
[0432] 1.1.b) Preparation of the Final Product
[0433] According to GWP 5, in the case of the reaction of
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxyl}phenyl)-N,N-dimethyl-formimidamide (50 mg, 0.1
mmol) with isopropylamine (0.01 ml, 0.12 mmol) the desired product
is obtained after chromatographic purification (silica gel,
dichloromethane/methanol: 0.fwdarw.20% methanol) in 78% yield (40
mg).
[0434] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 1.07 (t, 3H), 1.25
(d, 6H), 3.48 (s, 3H), 3.84-3.95 (m, 2H), 4.43-4.51 (m, 1H), 5.50
(s, 2H), 7.33 (s, 1H), 7.77 (t, 1H), 7.89-7.97 (m, 3H), 8.15 (s,
1H), 8.43 (s, 1H), 8.72 (s, 1H).
EXAMPLE 1.2
(RS)-S-[3-({[6-Bromo-4-(isopropylamino)quinazolin-7-yl]oxy}methyl)phenyl]--
S-methylsulphoximide
##STR00020##
[0436] According to GWP 6, in the case of the reaction of
(RS)-S-[3-({[6-bromo-4-(isopropylamino)quinazolin-7-yl]oxyl}methyl)phenyl-
]-N-(ethoxycarbonyl)-S-methylsulphoximide (100 mg, 0.19 mmol), the
desired product is obtained after chromatographic purification
(silica gel, dichloromethane/methanol: 0.fwdarw.20% methanol) in
61% yield (52 mg).
[0437] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 1.25 (d, 6H), 3.09
(s, 3H), 4.28 (s, 1H), 4.43-4.51 (m, 1H), 5.47 (s, 2H), 7.32 (s,
1H), 7.68 (t, 1H), 7.80 (d, 1H), 7.92-7.95 (m, 2H), 8.13 (s, 1H),
8.42 (s, 1H), 8.71 (s, 1H).
EXAMPLE 1.3
[0438]
(RS)-S-{3-[({6-Bromo-4-[(cyclopropylmethyl)amino]quinazolin-7-yl}ox-
y)methyl]-phenyl}-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00021##
[0439] According to GWP 5, in the case of the reaction of
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethyl-formimidamide (50 mg, 0.1
mmol) with cyclopropylmethylamine (8.4 mg, 0.12 mmol), the desired
product is obtained after chromatographic purification in 76% yield
(40 mg).
[0440] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 0.26-0.31 (m, 2H),
0.47-0.51 (m, 2H), 1.05-1.17 (m, 4H), 3.37-3.41 (m, 2H), 3.48 (s,
3H), 3.48-3.95 (m, 2H), 5.50 (s, 2H), 7.35 (s, 1H), 7.77 (t, 1H),
7.89-7.97 (m, 2H), 8.15 (s, 1H), 8.37 (t, 1H), 8.42 (s, 1H), 8.69
(s, 1H).
EXAMPLE 1.4
(RS)-S-{3-[({6-Bromo-4-[(cyclopropylmethyl)amino]quinazolin-7-yl}oxy)methy-
l]-phenyl}-S-methylsulphoximide
##STR00022##
[0442] According to GWP 6, in the case of the reaction of
(RS)-S-{3-[({6-bromo-4-[(cyclo-propylmethyl)amino]quinazolin-7-yl}oxy)met-
hyl]phenyl}-N-(ethoxycarbonyl)-S-methyl-sulphoximide (40 mg, 0.075
mmol), the desired product is obtained after chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.30%
methanol) in 90% yield (31 mg).
[0443] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 0.26-0.31 (m, 2H),
0.45-0.51 (m, 2H), 1.15-1.19 1H), 3.09 (s, 3H), 3.36-3.41 (m, 2H),
4.27 (s, 1H), 5.48 (s, 2H), 7.34 (s, 1H), 7.68 (t, 1H), 7.80 (d,
1H), 7.93 (d, 1H), 8.13 (s, 1H), 8.36 (t, 1H), 8.42 (s, 1H), 8.69
(s, 1H).
EXAMPLE 1.5
(RS)-S-{3-[({6-Bromo-4-[(4-hydroxyphenyl)amino]quinazolin-7-yl}oxy)methyl]-
-phenyl}-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00023##
[0445] According to GWP 5, in the case of the reaction of
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethyl-formimidamide (53 mg, 0.1
mmol) with 4-aminophenol (13.7 mg, 0.13 mmol), the desired product
is obtained after chromatographic purification (silica gel,
hexane/ethyl acetate: 0.fwdarw.100% ethyl acetate, then
dichloromethane/methanol 0.fwdarw.20% methanol) in quantitative
yield (60 mg).
[0446] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 1.07 (t, 3H), 3.49
(s, 3H), 3.85-3.96 (m, 2H), 5.53 (s, 2H), 6.79 (d, 2H), 7.41 (s,
1H), 7.52 (d, 2H), 7.78 (t, 1H), 7.90-7.98 (m, 2H), 8.17 (s, 1H),
8.47 (s, 1H), 8.90 (s, 1H), 9.33 (s, 1H).
EXAMPLE 1.6
(RS)-S-[3-({[6-Bromo-4-(1H-pyrazol-3-ylamino)quinazolin-7-yl]oxy}methyl)-p-
henyl]-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00024##
[0448] According to GWP 5, in the case of the reaction of
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethyl-formimidamide (50 mg, 0.1
mmol) with 3-aminopyrazole (9.8 mg, 0.12 mmol), the desired product
is obtained after chromatographic purification (silica gel,
dichloromethane/methanol: 0.fwdarw.30% methanol) in 77% yield (42
mg).
[0449] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.03 (t, 3H), 3.44
(s, 3H), 3.83-3.92 (m, 2H), 5.49 (s, 2H), 6.79 (s, 1H), 7.38 (s,
1H), 7.65 (s, 1H), 7.73 (t, 1H), 7.87 (d, 1H), 7.92 (d, 1H), 8.12
(s, 1H), 8.52 (s, 1H), 9.04 (s, 1H), 10.41 (s, 1H), 12.46 (s,
1H).
EXAMPLE 1.7
(RS)-S-[3-({[6-Bromo-4-(1H-pyrazol-3-ylamino)quinazolin-7-yl]oxy}methyl)-p-
henyl]-S-methylsulphoximide
##STR00025##
[0451] According to GWP 6, in the case of the reaction of
(RS)-S-[3-({[6-bromo-4-(1
H-pyrazol-3-ylamino)quinazolin-7-yl]oxy}methyl)phenyl]-N-(ethoxycarbonyl)-
-S-methyl-sulphoximide (40 mg, 0.073 mmol), the desired product is
obtained after chromatographic purification (silica gel,
dichloromethane/methanol: 0.fwdarw.30% methanol) in 35% yield (12
mg).
[0452] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 3.05 (s, 3H), 4.25
(s,1 H), 5.46 (s, 2H), 6.79 (s, 1H), 7.37 (s, 1H), 7.63-7.67 (m,
2H), 7.78 (d, 1H), 7.89 (d, 1H), 8.09 (s, 1H), 8.52 (s, 1H), 9.04
(s, 1H), 10.4 (s, 1H), 12.46 (s, 1H).
EXAMPLE 1.8
(RS)-S-{3-[({6-Bromo-4-[(2-methoxyethyl)amino]quinazolin-7-yl}oxy)methyl]--
phenyl}-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00026##
[0454] According to GWP 5, in the case of the reaction of
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethyl-formimidamide (50 mg, 0.1
mmol) with 2-methoxyethylamine (8.9 mg, 0.12 mmol) the desired
product is obtained after chromatographic purification (silica gel,
dichloro-methane/methanol: 0.fwdarw.30% methanol) in 95% yield (50
mg).
[0455] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.02 (t, 3H), 3.24
(s, 3H), 3.44 (s, 3H), 3.52 (t, 2H), 3.64 (q, 2H), 3.82-3.90 (m,
2H), 5.46 (s, 2H), 7.31 (s, 1H), 7.72 (t, 1H), 7.86 (d, 1H), 7.91
(d, 1H), 8.11 (s, 1H), 8.28 (t, 1H), 8.40 (s, 1H), 8.63 (s,
1H).
EXAMPLE 1.9
(RS)-S-{3-[({6-Bromo-4-[(2-methoxyethyl)amino]quinazolin-7-yl}oxy)methyl]--
phenyl}-S-methylsulphoximide
##STR00027##
[0457] According to GWP 6, in the case of the reaction of
(RS)-S-{3-[({6-bromo-4-[(2-methoxyethyl)amino]quinazolin-7-yl}oxy)methyl]-
phenyl}-N-(ethoxycarbonyl)-S-methyl-sulphoximide (45 mg, 0.084
mmol) the desired product is obtained after chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.25%
methanol) in 92% yield (36 mg).
[0458] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 3.09 (s, 3H), 3.29
(s, 3H), 3.56 (t, 2H), 3.68 (q, 2H), 4.28 (s, 1H), 5.48 (s, 2H),
7.34 (s, 1H), 7.68 (t, 1H), 7.80 (d, 1H), 7.93 (d, 1H), 8.13 (s,
1H), 8.33 (t, 1H), 8.44 (s, 1H), 8.67 (s, 1H).
EXAMPLE 1.10
(RS)-S-(3-{[(6-Bromo-4-{[2-(dimethylamino)ethyl]amino}quinazolin-7-yl)oxy]-
-methyl}phenyl)-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00028##
[0460] According to GWP 5, in the case of the reaction of
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethyl-formimidamide (50 mg, 0.1
mmol) with N,N-dimethylethylenediamine (0.013 ml, 0.12 mmol) the
desired product is obtained after chromatographic purification
(silica gel, dichloromethane/methanol: 0.fwdarw.30% methanol) in
94% yield (51 mg).
[0461] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.02 (t, 3H), 2.16
(s, 6H), 3.26-3.28 (m, water+2H), 3.44 (s, 3H), 3.57 (q, 2H),
3.81-3.90 ( m, 2H), 5.45 (s, 2H), 7.30 (s, 7.72 (t, 1H), 7.86 (d,
1H), 7.91 (d, 1H), 8.11 (s, 1H), 8.15 (t, 1H), 8.39 (s, 1H), 8.60
(s, 1H).
EXAMPLE 1.11
(RS)-S-(3-{[(6-Bromo-4-{[2-(dimethylamino)ethyl]amino}quinazolin-7-yl)oxy]-
-methyl}phenyl)-S-methylsulphoximide
##STR00029##
[0463] According to GWP 6, in the case of the reaction of
(RS)-S-(3-{[(6-bromo-4-{[2-(dimethylamino)ethyl]amino}quinazolin-7-yl)oxy-
]methyl}phenyl)-N-(ethoxycarbonyl)-S-methylsulphoximide (45 mg,
0.082mmol) the desired product is obtained after chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.25%
methanol) in 85% yield (33 mg).
[0464] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 2.23 (s, 6H), 3.09
(s, 3H), 3.31-3.33 (water, 2H), 3.62 (q, 2H), 4.28 (s, 1H), 5.48
(s, 2H), 7.34 (s, 1H), 7.68 (t, 1H), 7.80 (d, 1H), 7.93 (d, 1H),
8.12 (s, 1H), 8.21 (t, 1H), 8.43 (s, 1H), 8.64 (s, 1H).
EXAMPLE 1.12
(RS)-S-[3-{[6-Bromo-4-(cyclopropylamino)quinazolin-7-yl]oxy}methyl)phenyl]-
-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00030##
[0466] According to GWP 5, in the case of the reaction of
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethyl-formimidamide (50 mg, 0.1
mmol) with cyclopropylamine (6.7 mg, 0.12 mmol), the desired
product is obtained after chromatographic purification (silica gel,
dichloro-methane/methanol: 0.fwdarw.30% methanol) in 98% yield (50
mg).
[0467] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 0.58-0.61 (m, 2H),
0.73-0.78 (m, 2H), 1.02 (t, 3H), 2.96-3.00 (m, 1H), 3.44 (s, 3H),
3.80-3.90 (m, 2H), 5.45 (s, 2H), 7.31 (s, 1H), 7.72 (t, 1H), 7.85
(d, 1H), 7.91 (d, 1H), 8.11 (s, 1H), 8.17 (d, 1H), 8.45 (s, 1H),
8.58 (s, 1H).
EXAMPLE 1.13
(RS)-S-[3-({[6-Bromo-4-(cyclopropylamino)quinazolin-7-yl]oxy}methyl)phenyl-
]-S-methylsulphoximide
##STR00031##
[0469] According to GWP 6, in the case of the reaction of
(RS)-S-[3-({[6-bromo-4-(cyclo-propylamino)quinazolin-7-yl]oxy}methyl)phen-
yl]-N-(ethoxycarbonyl)-S-methylsulphox-imide (45 mg, 0.087 mmol),
the desired product is obtained after chromatographic purification
(silica gel, dichloromethane/methanol: 0.fwdarw.30% methanol) in
83% yield (32 mg).
[0470] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 0.61-0.66 (m, 2H),
0.77-0.83 (m, 2H), 2.99-3.06 (m, 1H), 3.09 (s, 3H), 4.28 (s, 1H),
5.47 (s, 2H), 7.35 (s, 1H), 7.68 (t, 1H), 7.80 (d, 1H), 7.93 (d,
1H), 8.12 (s, 1H), (8.22 (d, 1H), 8.49 (s, 1H), 8.62 (s, 1H).
EXAMPLE 1.14
(RS)-S-[3-({[6-Bromo-4-(cyclobutylamino)quinazolin-7-yl]oxy}methyl)phenyl]-
-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00032##
[0472] According to GWP 5, in the case of the reaction of
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethylformimidamide (50 mg, 0.1 mmol)
with cyclobutylamine (8.4 mg, 0.12 mmol) the desired product is
obtained after chromatographic purification (silica gel,
dichloromethane/methanol: 0.fwdarw.30% methanol) in 94% yield (49
mg).
[0473] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.02 (t, 3H),
1.64-1.73 (m, 2H), 2.02-2.12 (m, 2H), 2.25-2.32 (m, 2H), 3.44 (s,
3H), 3.81-3.90 (m, 2H), 4.61-4.67 (m, 1H), 5.45 (s, 2H), 7.29 (s,
1H), 7.72 (t, 1H), 7.85 (d, 1H), 7.91 (d, 1H), 8.11 (s, 1H), 8.28
(d, 1H), 8.37 (s, 1H), 8.68 (s, 1H).
EXAMPLE 1.15
(RS)-S-({[3-(1[6-Bromo-4-(cyclobutylamino)quinazolin-7-yl]oxy}methyl)pheny-
l]-S-methylsulphoximide
##STR00033##
[0475] According to GWP 6, in the case of the reaction of
(RS)-S-[3-({[6-bromo-4-(cyclo-butylamino)quinazolin-7-yl]oxy}methyl)pheny-
l]-N-(ethoxycarbonyl)-S-methylsulphox-imide (45 mg, 0.084 mmol),
the desired product is obtained after chromatographic purification
(silica gel, dichloromethane/methanol: 0.fwdarw.25% methanol) in
88% yield (34 mg).
[0476] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 1.67-1.79 (m, 2H),
2.05-2.20 (m, 2H), 2.28-2.35 (m, 2H), 3.09 (s, 3H), 4.28 (s, 1H),
4.60-4.75 (m, 1H), 5.47 (s, 2H), 7.33 (s, 1H), 7.68 (t, 1H), 7.80
(d, 1H), 7.93 (d, 1H), 8.12 (s, 1H), 8.33 (d, 1H), 8.42 (s, 1H),
8.72 (d, 1H).
EXAMPLE 1.16
Ethyl
7-({(RS)-3-[N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyl}oxy)-4--
(isopropylamino)quinazoline-6-carboxylate
##STR00034##
[0478] 1.16.a) Preparation of the Intermediates
Compound 1.16.a.1
Ethyl-4-amino-5-cyano-2-hydroxybenzoate
##STR00035##
[0480] According to H.-W-. Schmidt et al. (Liebigs Ann. Chem. 1979,
2005-10), ethyl acetate (42 g, 323 mmol) is added to a solution of
sodium (15 g, 23 mmol) in ethanol (4.0 l) and the mixture is
stirred at room temperature for 30 minutes.
Ethoxymethylene-malononitrile (40.6 g, 332 mmol) is added. After 30
minutes at 80.degree. C., the reaction mixture is allowed to cool
to room temperature and the resulting precipitate is filtered off
with suction. The precipitate is dissolved using water, and the
aqueous phase is acidified with concentrated hydrochloric acid and
the resulting precipitate is filtered off with suction again. After
recrystallization from acetic acid, the crystals are filtered off
with suction, washed with water and subsequently dried. The desired
product is obtained in 29% yield (21.5 g).
[0481] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.30 (t, 3H), 4.28
(q, 2H), 6.20 (s, 1H), 6.80 (br s, 2H), 7.89 (s, 1H), 10.99 (s,
1H).
Compound 1.16.a.2
Ethyl
5-cyano-4-{(E/Z)-[(dimethylamino)methylene]amino}-2-hydroxybenzoate
##STR00036##
[0483] Ethyl 4-amino-5-cyano-2-hydroxybenzoate (8.3 g, 40.25 mmol)
and dimethyl-formamide dimethyl acetal (38.4 g, 322 mmol) are
combined and stirred at room temperature for 2 hours. The
precipitate resulting during the reaction is filtered off with
suction and washed with diethyl ether (7.0 g). The filtrate is
concentrated and purified by chromatography (eluent:
dichloromethane/methanol). The solid obtained in this way is
stirred with diethyl ether, and subsequently filtered off with
suction and dried (1.8 g). Altogether, the desired product is
obtained in 83% yield (8.8 g).
[0484] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.33 (t, 3H), 3.02
(s, 3H), 3.11 (s, 3H), 4.34 (q, 2H), 6.72 (s, 1H), 8.00 (s, 1H),
8.12 (s, 1H), 11.04 (s, 1H).
Compound 1.16.a.3
Ethyl
5-cyano-4-{(E/Z)-[(dimethylamino)methylene]amino}-2-({(RS)-3-[N-(eth-
oxycarbonyl)-S-methylsulphonimidoyl]benzyl}oxy)benzoate
##STR00037##
[0486] Ethyl
5-cyano-4-{(E/Z)-[(dimethylamino)methylene]amino}-2-hydroxybenzoate
(30 mg, 0.12 mmol) and
(RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-methyl-sulphoximide
(56 mg, 0.15 mmol) are dissolved in 1 ml of tetrahydrofuran. After
addition of potassium carbonate (48 mg, 0.35 mmol), the reaction
mixture is boiled at 50.degree. C. for 20 hours. The batch is
diluted with ethyl acetate, and the organic phase is washed with
water and dried over sodium sulphate. After removing the solvent,
the residue is reacted further as the crude product (64 mg,
84%).
[0487] LC-MS (Instrument: Micromass Quattro LCZ with HPLC Agilent
Series 1100; column: Phenomenex Synergi 2.5.mu. MAX-RP 100A Mercury
20 mm.times.4 mm; eluent A: 1 l of water+0.5 ml of 50% strength
formic acid, eluent B: 1 l of acetonitrile+0.5 ml of 50% strength
formic acid; gradient: 0.0 min 90% A.fwdarw.0.1 min 90%A.fwdarw.3.0
min 5% A.fwdarw.4.0 min 5% A.fwdarw.4.1 min 90% A; flow: 2 ml/min;
oven: 50.degree. C.; UV detection: 208-400 nm):Rt=1.78 min; MS (ESI
pos.): m/z=501 (M+H.sup.+).
[0488] 1.16.b) Preparation of the Final Product
[0489] According to GWP 5, ethyl
5-cyano-4-{(E/Z)-[(dimethylamino)methylene]amino}-2-({(RS)-3-[N-(ethoxyca-
rbonyl)-S-methylsulphonimidoyl]benzyl}(oxy)benzoate (60 mg, 0.12
mmol) is reacted with isopropylamine (9.2 mg, 0.16 mmol). After
cooling, the reaction mixture was diluted with water and sodium
hydroxide solution (1N). The organic phase is separated off and
dried over sodium sulphate. After concentrating the solvent, the
residue (55 mg, 72%) is employed in the next reaction without
further purification.
[0490] LC-MS (apparatus type MS: Micromass ZQ; apparatus type HPLC:
Waters Alliance 2795; column: Phenomenex Synergi 2.5.mu. MAX-RP
100A Mercury 20 mm.times.4 mm; eluent A: 1 l water+0.5 ml 50%
strength formic acid, eluent B: 1 l of acetonitrile+0.5 ml of 50%
strength formic acid; gradient: 0.0 min 90% A.fwdarw.0.1 min 90%
A.fwdarw.3.0 min 5% A.fwdarw.4.0 min 5% A.fwdarw.4.01 min 90% A;
flow: 2 ml/min; oven: 50.degree. C.; UV detection: 210
nm):R.sub.t=1.78 min; MS (ESI pos.): m/z=515 (M+H.sup.+).
EXAMPLE 1.17
4-(Isopropylamino)-7-{[(RS)-3-(S-methylsulphonimidoyl)benzyl]oxy}-quinazol-
ine-6-carboxylic acid
##STR00038##
[0492] According to GWP 6, ethyl
7-({(RS)-3-[N-(ethoxycarbonyl)-S-methylsulphonimidoyl]-benzyl}oxy)-4-(iso-
propylamino)quinazoline-6-carboxylate (100 mg, 0.194 mmol) is
reacted at 80.degree. C. for 2 hours with sodium ethoxide (59 mg,
0.9 mmol). The reaction mixture is concentrated to dryness. The
residue is taken up in ethyl acetate and water and acidified. The
organic phase is separated off and subsequently concentrated. After
chromatographic purification, the desired product is obtained in
35% yield (28 mg).
[0493] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.28 (d, 6H), 3.09
(s, 3H), 3.17 (s, 1H), 4.53-4.62 (m, 1H), 5.46 (s, 2H), 7.28 (s,
1H), 7.66 (t, 1H), 7.81 (d, 1H), 7.91 (d, 1H), 8.14 (s, 1H), 8.59
(s, 1H), 8.83 (s, 1H), 8.86 (br s, 1H), 13.25 (br s, 1H).
EXAMPLE 1.18
(RS)-S-[3-({[6-Bromo-4-(1,3,4-thiadiazol-2-ylamino)quinazolin-7-yl]oxy}met-
hyl)-phenyl]-S-methylsulphoximide
##STR00039##
[0495] According to GWP 5, in the case of the reaction of
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethylformimidamide (50 mg, 0.1 mmol)
with 2-amino-1,3,4-thiadiazole (12 mg, 0.12 mmol) 34 mg of product
is obtained after chromatographic purification (silica gel,
dichloromethane/methanol: 0.fwdarw.30% methanol), which is employed
in the next reaction.
[0496] According to GWP 6, in the case of the reaction of DSC3250
(32 mg), the desired product is obtained after chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.30%
methanol) in 38% yield (19 mg, over 2 stages).
[0497] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 3.05 (s, 3H), 4.22
(s, 1H), 5.39 (s, 2H), 7.12 (s, 1H), 7.64 (t, 1H), 7.77 (d, 1H),
7.87 (d, 1H), 8.09 (s, 1H), 8.32 (s, 1H), 8.52 (s, 1H), 8.68 (s,
1H).
EXAMPLE 1.19
(RS)-S-[3-({[4-(Cyclopropylamino)-6-methoxyquinazolin-7-yl]oxy}methyl)-phe-
nyl]-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00040##
[0499] 1.19.a) Preparation of the Intermediate
[0500]
N'-(2-Cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]be-
nzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide
##STR00041##
[0501]
(E/Z)-N'-(2-Cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylformimidam-
ide (850 mg, 3.88 mmol) and
(RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide
(1.86 g, 5.82 mmol) are suspended in 16 mL of acetone. After
addition of potassium carbonate (992 mg, 7.17 mmol), the reaction
mixture is refluxed for 6 hours. The batch is diluted with ethyl
acetate and the organic phase is washed with water and dried over
sodium sulphate to obtain, after removal of the solvent and also
chromatographic purification (silica gel, hexane,
dichloromethane/methanol: 0.fwdarw.10% methanol), the desired
product in 88% yield (1.57 g).
[0502] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.03 (t, 3H),
2.92 (s, 3H), 3.02 (s, 3H), 3.44 (s, 3H), 3.70 (s, 3H), 3.81-3.91
(m, 2H), 5.26 (s, 2H), 6.86 (s,1 H), 7.11 (s,1 H), 7.69 (t, 1H),
7.79 (d, 1H), 7.84 (s, 1H), 7.90 (d, 1H), 8.04 (s, 1H).
[0503] 1.19.b) Preparation of the Final Product
[0504] According to GWP 5, reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylox-
y}-4-methoxyphenyl)-N,N-dimethylformimidamide (72 mg, 0.16 mmol)
with cyclopropylamine (13 .mu.L, 0.19 mmol) and chromatographic
purification (silica gel, amino column, hexane,
dichloromethane/methanol: 0.fwdarw.5% methanol) gives the desired
product in 68% yield (50 mg).
[0505] .sup.1H-NMR (300 MHz, DMSO): .differential. 0.55-0.60 (m,
2H), 0.74-0.80 (m, 2H), 1.02 (t, 3H), 2.91-2.94 (m, 1H), 3.44 (s,
3H), 3.80-3.90 (m, 5H), 5.34 (s, 2H), 7.20 (s, 1H), 7.56 (s, 1H),
7.70 (t, 1H), 7.81 (d, 1H), 7.89-7.92 (m, 2H), 8.06 (s, 1H), 8.35
(s, 1H).
EXAMPLE 1.20
(RS)-S-[3-({[4-(Cyclopropylamino)-6-methoxyquinazolin-7-yl]oxy}methyl)-phe-
nyl]-S-methylsulphoximide
##STR00042##
[0507] According to GWP 6, the conversion of
(RS)-S-[3-({[4-(cyclopropylamino)-6-methoxy-quinazolin-7-yl]oxy}methyl)ph-
enyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (46 mg, 0.098 mmol)
and preparative thin layer chromatography (silica gel, ethyl
acetate/ethanol: 4/1) gives the desired product in 64% yield (25
mg).
[0508] .sup.1H-NMR (300 MHz, DMSO): .differential. 0.55-0.60 (m,
2H), 0.75-0.80 (m, 2H), 2.88-2.95 (m, 1H), 3.04 (s, 3H), 3.85 (s,
3H), 4.23 (s, 1H), 5.31 (s, 2H), 7.18 (s, 1H), 7.56 (s, 1H), 7.61
(t, 1H), 7.72 (d, 1H), 7.87-7.92 (m, 2H), 8.03 (s, 1H), 8.35 (s,
1H).
EXAMPLE 1.21
(RS)-S-[3-({[4-(Cyclobutylamino)-6-methoxyquinazolin-7-yl]oxy}methyl)pheny-
l]-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00043##
[0510] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylox-
y}-4-methoxyphenyl)-N,N-dimethylformimidamide (72 mg, 0.16 mmol)
with cyclobutylamine (16 .mu.L, 0.19 mmol) and chromatographic
purification (silica gel, amino column, hexane,
dichloromethane/methanol: 0.fwdarw.5% methanol) gives the desired
product in 74% yield (56 mg).
[0511] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.07 (t, 3H),
1.69-1.81 (m, 2H), 2.09-2.16 (m, 2H), 2.32-2.41 (m, 2H), 3.49 (s,
3H), 3.84-3.95 (m, 5H), 4.68-4.76 (m, 1H), 5.38 (s, 2H), 7.23 (s,
1H), 7.68 (s, 1H), 7.75 (t, 1H), 7.87 (d, 1H), 7.94-7.89 (m, 2H),
8.11 (s, 1H), 8.32 (s, 1H).
EXAMPLE 1.22
(RS)-S-[3-({[4-(Cyclobutylamino)-6-methoxyquinazolin-7-yl]oxy}methyl)pheny-
l]-S-methylsulphoximide
##STR00044##
[0513] According to GWP 6, the conversion of
(RS)-S-[3-({[4-(cyclobutylamino)-6-methoxy-quinazolin-7-yl]oxy}methyl)phe-
nyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (48 mg, 0.099 mmol)
and preparative thin layer chromatography (silica gel, ethyl
acetate/ethanol: 4/1) gives the desired product in 59% yield (24
mg).
[0514] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.64-1.76 (m,
2H), 2.01-2.11 (m, 2H), 2.23-2.35 (m, 2H), 3.04 (s, 3H), 3.88 (s,
3H), 4.23 (s, 1H), 4.60-4.70 (m, 1H), 5.31 (s, 7.17 (s, 1H),
7.59-7.64 (m, 2H), 7.73 (d, 1H), 7.87-7.94 (m, 2H), 8.03 (s, 1H),
8.27 (s, 1H).
EXAMPLE 1.23
(RS)-N-(Ethoxycarbonyl)-S-methyl-S-[3-({[6-methoxy-4-(4-pyridylamino)-quin-
azolin-7-yl]oxy}methyl)phenyl]sulphoximide
##STR00045##
[0516] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylox-
y}-4-methoxyphenyl)-N,N-dimethylformimidamide (78 mg, 0.12 mmol)
with 4-aminopyridine (19 mg, 0.20 mmol) and chromatographic
purification (silica gel, amino column, hexane,
dichloromethane/methanol: 0.fwdarw.5% methanol) gives the desired
product in 34% yield (29 mg).
[0517] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.07 (t, 3H),
3.50 (s, 3H), 3.85-3.96 (m, 2H), 4.02 (s, 3H), 5.46 (s, 2H), 7.43
(s, 1H), 7.77 (t, 1H), 7.89-7.98 (m, 5H), 8.14 (s, 8.50 (d, 2H),
8.64 (s, 1H), 9.75 (s, 1H).
EXAMPLE 1.24
(RS)-S-[3-({[6-Methoxy-4-(4-pyridylamino)quinazolin-7-yl]oxy}methyl)phenyl-
]-S-methylsulphoximide
##STR00046##
[0519] According to GWP 6, the conversion of
(RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[6-methoxy-4-(4-pyridylamino)quin-
azolin-7-yl]oxy}methyl)phenyl]sulphoximide (28 mg, 0.049 mmol) and
preparative thin layer chromatography (silica gel, ethyl
acetate/ethanol: 4/1) gives the desired product in 51% yield (11
mg).
[0520] .sup.1H-NMR (300 MHz, DMSO): .differential. 3.05 (s, 3H),
3.97 (s, 3H), 4.25 (s, 1H), 5.38 (s, 2H), 7.37 (s, 1H), 7.63 (t,
1H), 7.76 (d, 1H), 7.87-7.93 (m, 4H), 8.06 (s, 1H), 8.45 (d, 2H),
8.59 (s, 1H), 9.71 (s, 1H).
EXAMPLE 1.25
(RS)-N-(Ethoxycarbonyl)-S-methyl-S-[3-({[6-methoxy-4-(3-pyridylamino)-quin-
azolin-7-yl]oxy}methyl)phenyl]sulphoximide
##STR00047##
[0522] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylox-
y}-4-methoxyphenyl)-N,N-dimethylformimidamide (76 mg, 0.17 mmol)
with 3-aminopyridine (19 mg, 0.20 mmol) and chromatographic
purification (silica gel, amino column, hexane,
dichloromethane/methanol: 0.fwdarw.5% methanol) gives the desired
product in 55% yield (46 mg).
[0523] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.08 (t, 3H),
3.50 (s, 3H), 3.85-3.96 (m, 2H), 4.02 (s, 3H), 5.45 (s, 2H), 7.38
(s, 1H), 7.45 (dd, 1H), 7.76 (t, 1H), 7.89-7.99 (m, 3H), 8.14 (s,
1H), 8.24-8.27 (m, 1H), 8.32-8.34 (m, 1H), 8.50 (s, 1H), 8.96 (d,
1H), 9.60 (s, 1H).
EXAMPLE 1.26
(RS)-S-[3-({[6-Methoxy-4-(3-pyridylamino)quinazolin-7-yl]oxy}methyl)-pheny-
l]-S-methylsulphoximide
##STR00048##
[0525] According to GWP 6, the conversion of
(RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[6-methoxy-4-(3-pyridylamino)quin-
azolin-7-yl]oxy}methyl)phenyl]sulphoximide (42 mg, 0.083 mmol) and
preparative thin layer chromatography (silica gel, ethyl
acetate/ethanol: 4/1) gives the desired product in 64% yield (23
mg).
[0526] .sup.1H-NMR (300 MHz, DMSO): .differential. 3.05 (s, 3H),
3.95 (s, 3H), 4.25 (s, 1H), 5.37 (s, 2H), 7.32 (s, 1H), 7.40 (dd,
1H), 7.63 (t, 1H), 7.75 (d, 1H), 7.86 (s, 1H), 7.90 (d, 1H), 8.06
(s, 1H), 8.20-8.23 (m, 1H), 8.27-8.29 (m, 1H), 8.45 (s, 1H), 8.91
(d, 1H), 9.63 (s, 1H).
EXAMPLE 1.27
(RS)-N-(Ethoxycarbonyl)-S-methyl-S-[3-({[6-methoxy-4-(thiazol-2-ylamino)-c-
hinazolin-7-yl]oxy}methyl)phenyl]sulphoximide
##STR00049##
[0528] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylox-
y}-4-methoxyphenyl)-N,N-dimethylformimidamide (76 mg, 0.17 mmol)
with 2-aminothiazole (20 mg, 0.20 mmol) and chromatographic
purification (silica gel, amino column, hexane,
dichloromethane/methanol: 0.fwdarw.5% methanol) gives the desired
product in 67% yield (57 mg).
[0529] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.07 (t, 3H),
3.50 (s, 3H), 3.82-3.93 (m, 2H), 3.99 (s, 3H), 5.46 (s, 2H), 7.28
(d, 1H), 7.43 (s, 1H), 7.57 (d, 1H), 7.76 (t, 1H), 7.90 (d, 1H),
7.97 (d, 1H), 8.13 (s, 1H), 8.25 (br, 1H), 8.71 (s, 1H), 12.13 (s,
1H).
EXAMPLE 1.28
(RS)-S-[3-({[6-Methoxy-4-(thiazol-2-yl-amino)quinazolin-7-yl]oxy}methyl)-p-
henyl]-S-methylsulphoximide
##STR00050##
[0531] According to GWP 6, the conversion of
(RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[6-methoxy-4-(thiazolyl-2-amino)q-
uinazolin-7-yl]oxy}methyl)phenyl]-sulphoximide (51 mg, 0.099 mmol)
and stirring of the crude product in dichloromethane/methanol gives
the desired product in 48% yield (21 mg).
[0532] .sup.1H-NMR (300 MHz, DMSO): .differential. 3.05 (s, 3H),
3.94 (s, 3H), 4.25 (s, 1H), 5.38 (s, 2H), 7.21 (d, 1H), 7.37 (s,
1H), 7.52 (d, 1H), 7.63 (t, 1H), 7.75 (d, 1H), 7.90 (d, 1H ), 8.06
(s, 1H), 8.14 (s, 1H), 8.65 (s, 1H), 12.13 (s, 1H).
EXAMPLE 1.29
(RS)-N-(Ethoxycarbonyl)-S-methyl-S-[3-({[6-methoxy-4-(1,3,4-thiadiazol-2-y-
lamino)quinazolin-7-yl]oxy}methyl)phenyl]sulphoximide
##STR00051##
[0534] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylox-
y}-4-methoxyphenyl)-N,N-dimethylformimidamide (76 mg, 0.17 mmol)
with 2-amino-1,3,4-thiadiazole (20 mg, 0.20 mmol) and
chromatographic purification (silica gel, amino column, hexane,
dichloromethane/methanol: 0.fwdarw.5% methanol) gives the desired
product in 47% yield (40 mg).
[0535] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.02 (t, 3H),
3.45 (s, 3H), 3.80-3.90 (m, 2H), 3.95 (s, 3H), 5.42 (s, 2H), 7.41
(s, 1H), 7.72 (t, 1H), 7.85 (d, 1H), 7.92 (d, 1H), 8.09 (s, 1H),
8.15 (br, 1H), 8.69 (s, 1H), 9.16 (s, 1H), 12.5 (s, 1H).
EXAMPLE 1.30
(RS)-S-[3-({[6-Methoxy-4-(1,3,4-thiadiazol-2-ylamino)quinazolin-7-yl]oxy}--
methyl)phenyl]-S-methylsulphoximide
##STR00052##
[0537] According to GWP 6, the reaction of
(RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[6-methoxy-4-(1,3,4-thiadiazol-2--
ylamino)quinazolin-7-yl]oxy}methyl)phenyl]-sulphoximide (37 mg,
0.072 mmol) with sodium ethoxide (25 mg, 0.39 mmol) and
chromatographic purification (silica gel, hexane,
dichloromethane/methanol: 0.fwdarw.15% methanol) gives the desired
product in 35% yield (11 mg).
[0538] .sup.1H-NMR (300 MHz, DMSO): .differential. 3.05 (s, 3H),
3.95 (s, 3H), 4.25 (s,1 H), 5.39 (s, 2H), 7.40 (s, 1H), 7.63 (s,
1H), 7.75 (d, 1H), 7.90 (d, 1H), 8.06 (s, 1H), 8.15 (s, 8.68 (s,1
H), 9.15 (s, 1H), 12.5 (br, 1H).
EXAMPLE 1.31
(RS)-S-[3-({[4-(Cyclopropylamino)-6-methoxyquinazolin-7-yl]oxy}methyl)-phe-
nyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide
##STR00053##
[0540] 1.31.a) Preparation of the Intermediates
Compound 1.31.a.1
(RS)-N-(Ethoxycarbonyl)-S-ethyl-S-m-tolylsulphoximide
##STR00054##
[0542] According to GWP 3, the conversion of
(RS)-S-ethyl-S-(m-tolyl)sulphoximide (2.55 g, 13.91 mmol) and
chromatographic purification (silica gel, hexane/ethyl acetate:
0.fwdarw.100% ethyl acetate) gives the desired product in 92% yield
(3.27 g).
[0543] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.02-1.6 (m,
6H), 2.39 (s, 3H), 3.45-3.58 (m, 2H), 3.81-3.91 (m, 2H), 7.52-7.55
(m, 2H), 7.63-7.67 (m, 2H).
Compound 1.31.a.2
(RS)-S-[3-(Bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide
##STR00055##
[0545] According to GWP 4, the conversion of
(RS)-N-(ethoxycarbonyl)-S-ethyl-S-(m-tolyl)-sulphoximide (2.71 g,
11.2 mmol) and chromatographic purification (silica gel,
hexane/ethyl acetate: 0.fwdarw.100% ethyl acetate, followed by
ethyl acetate/methanol: 4/1) gives the desired product in 31% yield
(1.1 g).
[0546] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.01-1.08 (m,
6H), 3.47-3.61 (m, 2H), 3.81-3.92 (m, 2H), 4.80 (s, 2H), 7.65 (t,
1H), 7.78-7.81 (m, 2H), 7.96 (t, 1H).
Compound 1.31.a.3
N'-(2-Cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-ethylsulphonimidoyl]benzyloxy}-
-4-methoxyphenyl)-N,N-dimethylformimidamide
##STR00056##
[0548]
(E/Z)-N'-(2-Cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylformimidam-
ide (970 mg, 4.41 mmol) and
(RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide
(1.62 g, 4.85 mmol) are suspended in 18 mL of acetone. After
addition of potassium carbonate (1.13 g, 8.15 mmol), the reaction
mixture is refluxed for 6 hours. The batch is diluted with ethyl
acetate and the organic phase is washed with water and dried over
sodium sulphate to obtain, after removal of the solvent and also
chromatographic purification (silica gel, hexane/ethyl acetate:
0.fwdarw.100% ethyl acetate, followed by ethyl acetate/methanol:
4/1), the desired product in 85% yield (1.77 g).
[0549] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.01-1.06 (m,
6H), 2.92 (s, 3H), 3.02 (s, 3H), 3.49-3.59 (m, 2H), 3.71 (s, 3H),
3.78-3.92 (m, 2H), 5.28 (s, 2H), 6.84 (s, 1H), 7.10 (s, 1H), 7.70
(t, 1H), 7.79 (d, 1H), 7.82-7.83 (m, 2H), 7.97 (s, 1H).
[0550] 1.31.b) Preparation of the Final Product
[0551] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-ethylsulphonimidoyl]benzyloxy-
}-4-methoxyphenyl)-N,N-dimethylformimidamide (50 mg, 0.11 mmol)
with cyclopropylamine (7.3 mg, 0.13 mmol) and chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.30%
methanol) gives the desired product in 92% yield (47 mg).
[0552] .sup.1H-NMR (300 MHz, DMSO): .differential. 0.55-0.60 (m,
2H), 0.74-0.80 (m, 2H), 0.99-1.06 (m, 6H), 2.92-2.95 (m, 1H),
3.47-3.58 (m, 2H), 3.78-3.92 (m, 5H), 5.35 (s, 2H), 7.18 (s, 1H),
7.56 (s, 1H), 7.70 (t, 1H), 7.82-7.85 (m, 2H), 7.90 (d, 1H), 7.99
(s, 1H) 8.35 (s, 1H).
EXAMPLE 1.32
(RS)-S-[3-({[4-(Cyclopropylamino)-6-methoxyquinazolin-7-yl]oxy}methyl)-phe-
nyl]-S-ethylsulphoximide
##STR00057##
[0554] According to GWP 6, the conversion of
(RS)-S-[3-({[4-(cyclopropylamino)-6-methoxy-quinazolin-7-yl]oxy}methyl)ph-
enyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide (47 mg, 0.097 mmol)
and chromatographic purification (silica gel,
dichloromethane/methanol: 0.fwdarw.30% methanol) gives the desired
product in 92% yield (37 mg).
[0555] .sup.1H-NMR (300 MHz, DMSO): .differential. 0.60-0.65 (m,
2H), 0.78-0.85 (m, 2H), 1.05 (t, 3H), 2.94-3.00 (m, 1H), 3.09-3.19
(m, 2H), 3.90 (s, 3H), 4.23 (s, 1H), 5.37 (s, 2H), 7.22 (s, 1H),
7.60 (s, 1H), 7.66 (t, 1H), 7.78 (d, 1H), 7.87 (d, 1H), 7.95 (d,
1H), 8.02 (s, 1H), 8.39 (s, 1H).
EXAMPLE 1.33
(RS)-S-[3-({[4-(Cyclobutylamino)-6-methoxyquinazolin-7-yl]oxy}methyl)pheny-
l]-N-(ethoxycarbonyl)-S-ethylsulphoximide
##STR00058##
[0557] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-ethylsulphonimidoyl]benzyloxy-
}-4-methoxyphenyl)-N,N-dimethylformimidamide (50 mg, 0.11 mmol)
with cyclobutylamine (9.1 mg, 0.13 mmol) and chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.30%
methanol) gives the desired product in 91% yield (48 mg).
[0558] .sup.1H-NMR (300 MHz, DMSO): .differential. 0.99-1.06 (m,
6H), 1.64-1.76 (m, 2H), 2.02-2.15 (m, 2H), 2.23-2.36 (m, 2H),
3.47-3.60 (m, 2H), 3.76-3.92 (m, 5H), 4.60-4.75 (m, 1H), 5.35 (s,
2H), 7.16 (s, 1H), 7.63 (s, 1H), 7.70 (t, 1H), 7.82-7.85 (m, 2H),
7.93 (d, 1H), 7.99 (s, 1H), 8.27 (s, 1H).
EXAMPLE 1.34
(RS)-S-[3-({[4-(Cyclobutylamino)-6-methoxyquinazolin-7-yl]oxy}methyl)-phen-
yl]-S-ethylsulphoximide
##STR00059##
[0560] According to GWP 6, the conversion of
(RS)-S-[3-({[4-(cyclobutylamino)-6-methoxy-quinazolin-7-yl]oxy}methyl)phe-
nyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide (48 mg, 0.096 mmol) and
chromatographic purification (silica gel, dichloromethane/methanol:
0.fwdarw.30% methanol) gives the desired product in 94% yield (39
mg).
[0561] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.01 (t, 3H),
1.65-1.75 (m, 2H), 2.03-2.13 (m, 2H), 2.27-2.34 (m, 2H), 3.06-3.14
(m, 2H), 3.89 (s, 3H), 4.20 (s, 1H), 4.62-4.73 (m, 1H), 5.32 (s,
2H), 7.15 (s, 1H), 7.60-7.64 (m, 2H), 7.74 (d, 1H), 7.82 (d, 1H),
7.94 (d, 1H), 7.97 (s, 1H), 8.27 (s, 1H).
EXAMPLE 1.35
(RS)-N-(Ethoxycarbonyl)-S-ethyl-S-[3-({[6-methoxy-4-(thiazol-2-ylamino)-qu-
inazolin-7-yl]oxy}methyl)phenyl]sulphoximide
##STR00060##
[0563] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-ethylsulphonimidoyl]benzyloxy-
}-4-methoxyphenyl)-N,N-dimethylformimidamide (50 mg, 0.11 mmol)
with 2-aminothiazole (12.8 mg, 0.13 mmol) and chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.30%
methanol) gives the desired product in 72% yield (40 mg).
[0564] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.00-1.07 (m,
6H), 3.49-3.60 (m, 2H), 3.78-3.91 (m, 2H), 3.94 (s, 3H), 5.43 (s,
2H), 7.23 (br, 1H), 7.37 (s, 1H), 7.53 (d, 1H), 7.72 (t, 1H),
7.84-7.87 (m, 2H), 8.02 (s, 1H), 8.17 (br, 1H), 8.65 (s, 1H), 12.07
(s, 1H).
EXAMPLE 1.36
(RS)-S-Ethyl-S-[3-({[6-methoxy-4-(thiazol-2-ylamino)quinazolin-7-yl]oxy}-m-
ethyl)phenyl]sulphoximide
##STR00061##
[0566] According to GWP 6, the conversion of
(RS)-N-(ethoxycarbonyl)-S-ethyl-S-[3-({[6-methoxy-4-(thiazol-2-ylamino)qu-
inazolin-7-yl]oxy}methyl)phenyl]-sulphoximide (40 mg, 0.076 mmol)
and chromatographic purification (silica gel,
dichloromethane/methanol: 0.fwdarw.30% methanol) gives the desired
product in 66% yield (23 mg).
[0567] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.01 (t, 3H),
3.09 (q, 2H), 3.94 (s, 3H), 4.23 (br, 1H), 5.40 (s, 2H), 7.23 (s,
1H), 7.36 (s, 1H), 7.63 (t, 1H), 7.76 (d, 1H), 7.84 (d, 1H), 8.00
(s, 1H), 8.15 (br, 1H), 8.65 (s, 1H), 12.08 (br, 1H).
EXAMPLE 1.37
(RS)-S-Ethyl-S-[3-({[6-methoxy-4-(1H-pyrazol-3-ylamino)quinazolin-7-yl]oxy-
}-methyl)phenyl]sulphoximide
##STR00062##
[0569] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-ethylsulphonimidoyl]benzyloxy-
}-4-methoxyphenyl)-N,N-dimethylformimidamide (50 mg, 0.11 mmol)
with 3-aminopyrazole (10.6 mg, 0.13 mmol) and chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.30%
methanol) gives 44 g of product which is subsequently reacted with
sodium ethoxide (19 mg, 0.31 mmol) according to GWP 6.
[0570] Chromatographic purification (silica gel,
dichloromethane/methanol: 0.fwdarw.30% methanol) gives via 2 stages
the desired product in 55% yield (26 mg).
[0571] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.06 (t, 3H),
3.10-3.20 (m, 2H), 3.96 (s, 3H), 4.25 (s, 1H), 5.41 (s, 2H), 6.83
(s, 1H), 7.29 (s, 1H), 7.65-7.70 (m, 2H), 7.80 (d, 7.87 (d, 1H),
8.03 (s, 2H), 8.46 (s, 1H), 10.23 (s, 1H), 12.43 (s, 1H).
EXAMPLE 1.38
(RS)-S-Ethyl-S-[3-({[6-methoxy-4-(oxazo-3-ylamino)quinazolin-7-yl]oxy}-met-
hyl)phenyl]sulphoximide
##STR00063##
[0573] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-ethylsulphonimidoyl]benzyloxy-
}-4-methoxyphenyl)-N,N-dimethylformimidamide (50 mg, 0.11 mmol)
with 2-aminooxazole (11 mg, 0.13 mmol) and chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.30%
methanol) gives 39 g of product which is subsequently reacted with
sodium ethoxide (17 mg, 0.27 mmol) according to GWP 6.
[0574] Chromatographic purification (silica gel,
dichloromethane/methanol: 0.fwdarw.30% methanol) gives via 2 stages
the desired product in 33% yield (16 mg).
[0575] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.01 (t, 3H),
3.09 (q, 2H), 3.90 (s, 3H), 4.21 (s, 1H), 5.38 (s, 2H), 7.23 (d,
1H), 7.28 (s, 1H), 7.63 (t, 1H), 7.69 (s, 1H), 7.75 (d, 1H), 7.77
(d, 1H), 7.83 (d, 1H), 7.98 (s, 1H), 8.30 (d, 1H), 13.37 (s,
1H).
EXAMPLE 1.39
(RS)-S-[3-({[6-Methoxy-4-(oxazo-3-ylamino)quinazolin-7-yl]oxy}methyl)pheny-
l]-S-methylsulphoximide
##STR00064##
[0577] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylox-
y}-4-methoxyphenyl)-N,N-dimethylformimidamide (142 mg, 0.31 mmol)
with 2-aminooxazole (32 mg, 0.37 mmol) and chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.10%
methanol) gives 91 mg of product which is subsequently reacted with
sodium ethoxide (40 mg, 0.65 mmol) according to GWP 6.
[0578] Preparative thin layer chromatography (silica gel,
dichloromethane/methanol: 9/1) gives via 2 stages the desired
product in 9% yield (12 mg).
[0579] .sup.1H-NMR (400 MHz, DMSO): .differential. 3.05 (s, 3H),
3.90 (s, 3H), 4.25 (s, 1H), 5.37 (s, 2H), 7.23 (d, 1H), 7.30 (s,
1H), 7.63 (t, 1H), 7.70 (s, 1H), 7.74 (d, 1H), 7.77 (d, 1H), 7.89
(d, 1H), 8.04 (s, 1H), 8.31 (d, 1H), 13.37 (s, 1H).
EXAMPLE 1.40
(RS)-S-(3-{[(6-Bromo-4-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}quinazolin-
-7-yl)oxy]methyl}phenyl)-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00065##
[0581] According to GWP 5, the reaction of
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethyl-formimidamide (113 mg, 0.22
mmol) with 2-amino-1,3-propanediol (25 mg, 0.27 mmol) and
chromatographic purification (silica gel, dichloromethane/methanol:
0.fwdarw.10% methanol) gives the desired product in 44% yield (54
mg).
[0582] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.07 (t, 3H)
3.49 (s, 3H), 3.79-3.95 (m, 4H), 4.40-4.52 (m, 2H), 4.95 (m, 1H),
5.21 (t, 1H), 5.54 (s, 2H), 7.42 (s,1 H), 7.77 (t, 1H), 7.89 (d,
1H), 7.96 (d, 1H), 8.15 (s, 1H), 8.30 (s, 1H), 8.44 (s, 1H).
EXAMPLE 1.41
(RS)-S-(3-{[(6-Bromo-4-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}quinazolin-
-7-yl)oxy]methyl}phenyl)-S-methylsulphoximide
##STR00066##
[0584] According to GWP 6, the conversion of
(RS)-S-(3-{[(6-bromo-4-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}quinazoli-
n-7-yl)oxy]methyl}phenyl)-N-(ethoxycarbonyl)-S-methylsulphoximide
(45 mg, 0.081 mmol) and preparation thin layer chromatography
(silica gel, dichloromethane/methanol: 4/1) gives the desired
product in 24% yield (9 mg).
[0585] .sup.1H-NMR (300 MHz, DMSO): .differential. 3.09 (s, 3H),
3.70-3.87 (m, 4H), 4.28 (s, 1H), 4.76 (m, 1H), 5.02 (t, 2H), 5.51
(s, 2H), 7.41 (s, 1H), 7.70 (d, 1H), 7.93 (d, 1H), 8.12 (s, 1H),
8.29(s, 1H), 8.31 (s, 1H).
EXAMPLE 1.42
(RS)-S-[3-({[6-Bromo-4-(2-hydroxyethylamino)quinazolin-7-yl]oxy}methyl)-ph-
enyl]-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00067##
[0587] According to GWP 5, the reaction of
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethyl-formimidamide (113 mg, 0.22
mmol) with 2-aminoethanol (0.016 mL, 0.27 mmol) and chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.10%
methanol) gives the desired product in 66% yield (77 mg).
[0588] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.07 (t, 3H)
3.48 (s, 3H), 3.57-3.63 (m, 4H), 3.84-3.98 (m, 2H), 4.81 (t, 1H),
5.50 (s, 2H), 7.35 (s, 1H), 7.77 (t, 1H), 7.90 (d, 1H), 7.96 (d,
1H), 8.15 (s, 1H), 8.29 (t, 1H), 8.43 (s, 1H), 8.67 (s, 1H).
EXAMPLE 1.43
(RS)-S-[3-({[6-Bromo-4-(2-hydroxyethylamino)quinazolin-7-yl]oxy}methyl)-ph-
enyl]-S-methylsulphoximide
##STR00068##
[0590] According to GWP 6,
(RS)-S-[3-({[6-bromo-4-(2-hydroxyethylamino)quinazolin-7-yl]oxy}methyl)ph-
enyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (67 mg, 0.13 mmol) is
reacted with sodium ethoxide (29 mg, 0.46 mmol) in ethanol (3 mL).
After cooling to room temperature, the reaction mixture is admixed
with brine and stirred for 30 minutes and the resulting precipitate
is filtered off with suction to leave the desired product in 81%
yield (47 mg).
[0591] .sup.1H-NMR (300 MHz, DMSO): .differential. 3.09 (s, 3H),
3.57-3.60 (m, 4H), 4.28 (s, 1H), 4.81 (br, 1H), 5.47 (s, 2H), 7.34
(s, 1H), 7.68 (t, 1H), 7.80 (d, 1H), 7.93 (d, 1H), 8.12 (s, 1H),
8.28 (t, 1H), 8.42 (s, 1H), 8.66 (s, 1H).
EXAMPLE 1.44
(RS)-N-(Ethoxycarbonyl)-S-methyl-S-[4-({[6-methoxy-4-(3-pyridylamino)-quin-
azolin-7-yl]oxy}methyl)phenyl]sulphoximide
##STR00069##
[0593] 1.44.a) Preparation of the Intermediate
[0594]
N'-(2-Cyano-5-{4-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]be-
nzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide
##STR00070##
[0595]
(E/Z)-N'-(2-Cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylformimidam-
ide (268 mg, 1.22 mmol) and
(RS)-S-[4-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide
(430 g, 1.34 mmol) are suspended in 5 mL of acetone. After addition
of potassium carbonate (312 mg, 2.26 mmol), the reaction mixture is
refluxed for 6 hours. The batch is diluted with ethyl acetate and
the organic phase is washed with water and dried over sodium
sulphate to obtain, after removal of the solvent and also
chromatographic purification (silica gel, hexane/ethyl acetate:
0.fwdarw.70% ethyl acetate, followed by ethyl acetate/methanol:
0.fwdarw.20% methanol), the desired product in 32% yield (180
mg).
[0596] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.09 (t, 3H),
2.97 (s, 3H), 3.07 (s, 3H), 3.48 (s, 3H), 3.76 (s, 3H), 3.86-3.97
(m, 2H), 5.31 (s, 2H), 6.89 (s, 1H), 7.16 (s, 1H), 7.74 (d, 2H),
7.89 (s, 1H), 8.00 (d, 2H).
[0597] 1.44.b) Preparation of the Final Product
[0598] According to GWP 5, the reaction of
N'-(2-cyano-5-{4-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylox-
y}-4-methoxyphenyl)-N,N-dimethylformimidamide (85 mg, 0.19 mmol)
with 3-aminopyridine (21 mg, 0.22 mmol) and chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.30%
methanol) gives the desired product in 42% yield (39 mg).
[0599] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.05 (t, 3H),
3.44 (s, 3H), 3.83-3.91 (m, 2H), 3.97 (s, 3H), 5.42 (s, 2H), 7.30
(s, 1H), 7.39 (dd, 1H), 7.76 (d, 2H), 7.86 (s, 1H), 7.97 (d, 2H),
8.19-8.22 (m, 1H), 8.28 (d, 1H), 8.45 (s, 1H), 8.92 (d, 1H), 9.63
(s, 1H).
EXAMPLE 1.45
(RS)-S-[4-({[6-Methoxy-4-(3-pyridylamino)quinazolin-7-yl]oxy}methyl)phenyl-
]-S-methylsulphoximide
##STR00071##
[0601] According to GWP 6, the conversion of
(RS)-N-(ethoxycarbonyl)-S-methyl-S-[4-({[6-methoxy-4-(3-pyridylamino)quin-
azolin-7-yl]oxy}methyl)phenyl]sulphoximide (33 mg, 0.064 mmol) and
chromatographic purification (silica gel, dichloromethane/methanol:
0.fwdarw.30% methanol) gives the desired product in 61% yield (17
mg).
[0602] .sup.1H-NMR (300 MHz, DMSO): .differential. 3.09 (s, 3H),
4.01 (s, 3H), 4.26 (s, 1H), 5.44 (s, 2H), 7.33 (s, 1H), 7.45 (dd,
1H), 7.73 (d, 2H), 7.90 (s, 1H), 7.99 (d, 2H), 8.24-8.27 (m, 1H),
8.32-8.34 (m, 1H), 8.49 (s, 1H), 8.95 (d, 1H), 9.68 (s, 1H).
EXAMPLE 1.46
(RS)-N-(Ethoxycarbonyl)-S-methyl-S-[4-({[6-methoxy-4-(1,3,4-thiadiazol-2-y-
l-amino)quinazolin-7-yl]oxy}methyl)phenyl]sulphoximide
##STR00072##
[0604] According to GWP 5, the reaction of
N'-(2-cyano-5-{4-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylox-
y}-4-methoxyphenyl)-N,N-dimethylformimidamide (85 mg, 0.19 mmol)
with 2-amino-1,3,4-thiadiazole (23 mg, 0.22 mmol) and
chromatographic purification (silica gel, dichloromethane/methanol:
0.fwdarw.30% methanol) gives the desired product in 40% yield (38
mg).
[0605] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.04 (t, 3H),
3.44 (s, 3H), 3.81-3.93 (m, 2H), 3.96 (s, 3H), 5.44 (s, 2H), 7.38
(s, 1H), 7.76 (d, 2H), 7.97 (d, 2H), 8.19 (s, 1H), 8.68 (s, 1H),
9.17 (s, 1H), 12.48 (s, 1H).
EXAMPLE 1.47
(RS)-S-[4-({[6-Methoxy-4-(1,3,4-thiadiazol-2-ylamino)quinazolin-7-yl]oxy}--
methyl)phenyl]-S-methylsulphoximide
##STR00073##
[0607] According to GWP 6, the conversion of
(RS)-N-(ethoxycarbonyl)-S-methyl-S-[4-({[6-methoxy-4-(1,3,4-thiadiazol-2--
ylamino)quinazolin-7-yl]oxy}methyl)-phenyl]sulphoximide (33 mg,
0.064 mmol) and chromatographic purification (silica gel,
dichloromethane/methanol: 0.fwdarw.30% methanol) gives the desired
product in 74% yield (21 mg).
[0608] .sup.1H-NMR (300 MHz, DMSO): .differential. 3.09 (s, 3H),
4.00 (s, 3H), 4.26 (s, 1H), 5.46 (s, 2H), 7.40 (s, 1H), 7.73 (d,
2H), 7.99 (d, 2H), 8.20 (s, 1H), 8.72 (s, 1H), 9.20 (s, 1H), 12.58
(s, 1H).
EXAMPLE 1.48
(RS)-S-[3-({[4-(Cyclopropylamino)quinazolin-7-yl]amino}methyl)phenyl]-N-(e-
thoxycarbonyl)-S-methylsulphoximide
##STR00074##
[0610] 1.48.a) Preparation of the Intermediates
Compound 1.48.a.1
N'-(5-Amino-2-cyanophenyl)-N,N-dimethylformimidamide
##STR00075##
[0612] N'-(2-Cyano-5-nitrophenyl)-N,N-dimethylformimidamide (1.0 g,
4.58 mmol) is dissolved in 100 mL of tetrahydrofuran, cooled to
0.degree. C. and admixed with titanium trichloride solution (69 mL
of a 15% solution in 10% aqueous HCl). Then, the batch is stirred
at room temperature for 4 hours and adjusted at 0.degree. C. to pH
9 with 2N aqueous sodium hydroxide solution. The mixture is diluted
with water and ethyl acetate. The aqueous phase is saturated with
sodium chloride and stirred out three times with ethyl acetate. The
combined organic phases are dried over sodium sulphate. Removal of
the solvent and also chromatographic purification (silica gel,
n-hexane/ethyl acetate:.fwdarw.100% ethyl acetate) gives the
desired product in 73% yield (630 mg).
[0613] .sup.1H-NMR (300 MHz, DMSO): .differential. 2.93 (s, 3H),
3.03 (s, 3H), 5.81 (s, 2H), 6.09 (d, 1H), 6.21 (dd, 1H), 7.18 (d,
1H), 7.70 (s, 1H).
Compound 1.48.a.2
N'-(2-Cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylami-
no}-phenyl)-N,N-dimethylformimidamide
##STR00076##
[0615] N'-(5-Amino-2-cyanophenyl)-N,N-dimethylformimidamide (50 mg,
0.27 mmol) and
(RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulph-
oximide (85 mg, 0.27 mmol) are dissolved in 4 mL of
dimethylformamide. After addition of potassium carbonate (68 mg,
0.49 mmol), the reaction mixture is stirred at 110.degree. C. for 4
hours. The batch is diluted with ethyl acetate and the organic
phase is washed with water and dried over sodium sulphate to leave,
after removal of the solvent and also after chromatographic
purification (silica gel, hexane/ethyl acetate: 0.fwdarw.100% ethyl
acetate), the desired product in 36% yield (40 mg).
[0616] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.01 (t, 3H),
2.88 (s, 3H), 2.97 (s, 3H), 3.40 (s, 3H), 3.77-3.86 (m, 2H), 4.42
(d, 2H), 6.11 (d, 1H), 6.24 (dd, 1H), 7.03 (t, 1H), 7.18 (d, 1H),
7.58-7.67 (m, 3H), 7.79 (d, 1H), 7.91 (s, 1H).
[0617] 1.48.b) Preparation of the Final Product
[0618] According to GWP 5, reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylam-
ino}phenyl)-N,N-dimethylformimidamide (80 mg, 0.19 mmol) with
cyclopropylamine (13 mg, 0.22 mmol) and chromatographic
purification (silica gel, n-hexane/ethyl acetate: 0.fwdarw.100%
ethyl acetate, followed by dichloromethane/methanol: 0.fwdarw.20%
methanol) gives the desired product in 74% yield (61 mg).
[0619] .sup.1H-NMR (300 MHz, DMSO): .differential. 0.55-0.60 (m,
2H), 0.74-0.78 (m, 2H), 1.03 (t, 3H), 2.91-2.97 (m, 1H), 3.44 (s,
3H), 3.81-3.91 (m, 2H), 4.53 (d, 2H), 6.49 (d, 1H), 6.90 (dd, 1H),
7.14 (t, 1H), 7.74-7.76 (m, 2H), 7.83 (d, 1H), 7.90 (d, 1H), 7.98
(s, 1H), 8.26 (s, 1H).
EXAMPLE 1.49
(RS)-S-[3-({[4-(Cyclopropylamino)quinazolin-7-yl]amino}methyl)phenyl]-S-me-
thylsulphoximide
##STR00077##
[0621] According to GWP 6, conversion of
(RS)-S-[3-({[4-(cyclopropylamino)quinazolin-7-yl]amino}methyl)phenyl]-N-(-
ethoxycarbonyl)-S-methylsulphoximide (58 mg, 0.13 mmol) and
chromatographic purification (silica gel, n-hexane/ethyl acetate:
0.fwdarw.100% ethyl acetate, followed by dichloromethane/methanol:
0.fwdarw.25% methanol) gives the desired product in 74% yield (36
mg).
[0622] .sup.1H-NMR (400 MHz, DMSO): .differential. 0.51-0.55 (m,
2H), 0.68-0.72 (m, 2H), 2.28-2.91 (m, 1H), 2.99 (s, 3H), 4.14 (s,
1H), 4.45 (d, 2H), 6.43 (d, 1H), 6.86 (dd, 1H), 7.09 (t, 1H), 7.53
(t, 1H), 7.60 (d, 1H), 7.72 (d, 1H), 7.77 (d, 1H), 7.85 (d, 1H),
7.92 (s, 1H), 8.21 (s, 1H).
EXAMPLE 1.50
(RS)-N-(Ethoxycarbonyl)-S-methyl-S-[3-({[4-(3-pyridylamino)quinazolin-7-yl-
]-amino}methyl)phenyl]sulphoximide
##STR00078##
[0624] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylam-
ino}phenyl)-N,N-dimethylformimidamide (50 mg, 0.12 mmol) with
3-aminopyridine (14 mg, 0.14 mmol) and chromatographic purification
(silica gel, dichloromethane/methanol: 0.fwdarw.30% methanol) gives
the desired product in 68% yield (38 mg).
[0625] .sup.1H-NMR (300 MHz, DMSO): .differential. 0.99 (t, 3H),
3.40 (s, 3H), 3.77-3.83 (m, 2H), 4.54 (d, 2H), 6.56 (d, 1H), 7.04
(dd, 1H), 7.30-7.34 (m, 2H), 7.63 (t, 1H), 7.73 (d, 1H), 7.80 (d,
1H), 7.96 (s, 1H), 8.17-8.24 (m, 3H), 8.32 (m, 1H), 8.91 (d, 1H),
9.48 (s, 1H)
EXAMPLE 1.51
(RS)-S-Methyl-S-[3-({[4-(3-pyridylamino)quinazolin-7-yl]amino}methyl)pheny-
l]-sulphoximide
##STR00079##
[0627] According to GWP 6, the conversion of
(RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[4-(3-pyridylamino)quinazolin-7-y-
l]amino}(methyl)phenyl]sulphoximide (35 mg, 0.073 mmol) and
chromatographic purification (silica gel, dichloromethane/methanol:
0.fwdarw.30% methanol) gives the desired product in 81% yield (24
mg).
[0628] .sup.1H-NMR (400 MHz, DMSO): .differential. 3.00 (s, 3H),
4.16 (s, 1H), 4.50 (d, 2H), 6.55 (d, 1H), 7.05 (dd, 1H), 7.31-7.35
(m, 2H), 7.54 (t, 1H), 7.63 (d, 1H), 7.78 (d, 1H), 7.95 (s, 1H),
8.17-8.25 (m, 3H), 8.32 (s, 1H), 8.91 (d, 1H), 9.49 (s, 1H).
EXAMPLE 1.52
(RS)-S-[3-({[4-(Isopropylamino)quinazolin-7-yl]amino}methyl)phenyl]-S-meth-
ylsulphoximide
##STR00080##
[0630] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylam-
ino}phenyl)-N,N-dimethylformimidamide (130 mg, 0.3 mmol) with
isopropylamine (0.031 mL, 0.36 mmol) and chromatographic
purification (silica gel, dichloromethane/methanol: 7/3) gives 150
mg of product which is subsequently reacted with sodium ethoxide
(104 mg, 1.7 mmol) according to GWP 6.
[0631] Chromatographic purification (silica gel,
dichloromethane/methanol: 0.fwdarw.20% methanol) gives via 2 stages
the desired product in 37% yield (49 mg).
[0632] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.21 (d, 6H),
3.04 (s, 3H), 4.19 (s, 1H), 4.42-4.51 (m, 3H), 6.46 (d, 1H), 6.91
(dd, 1H), 7.13 (t, 1H), 7.42 (d, 1H), 7.57 (t, 1H), 7.65 (d, 1H),
7.81 (d, 1H), 7.96-7.99 (m, 2H), 8.20 (s, 1H).
EXAMPLE 1.53
(RS)-S-Methyl-S-[3-({[4-(1,3,4-thiadiazol-2-ylamino)quinazolin-7-yl]amino}-
-methyl)phenyl]sulphoximide
##STR00081##
[0634] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylam-
ino}phenyl)-N,N-dimethylformimidamide (100 mg, 0.23 mmol) with
2-amino-1,3,4-thiadiazole (29 mg, 0.28 mmol) and chromatographic
purification (silica gel, n-hexane/ethyl acetate: 0.fwdarw.100%
ethyl acetate, followed by dichloromethane/methanol: 0.fwdarw.20%
methanol) gives 54 mg of product which is subsequently reacted with
sodium ethoxide (34 mg, 0.56 mmol) according to GWP 6.
Chromatographic purification (silica gel, n-hexane/ethyl acetate:
0.fwdarw.100% ethyl acetate, followed by dichloromethane/methanol:
0.fwdarw.25% methanol) gives via 2 stages the desired product in
23% yield (22 mg).
[0635] .sup.1H-NMR (400 MHz, DMSO): .differential. 3.05 (s, 3H),
4.20 (s, 1H), 4.56 (d, 2H), 6.63 (d, 1H), 7.10 (dd, 1H), 7.53 (t,
1H), 7.59 (t, 1H), 7.68 (d, 1H), 7.84 (d, 1H), 7.99 (s, 1H), 8.38
(br, 1H), 8.53 (s, 1H), 9.13 (s, 1H), 12.36 (br, 1H).
EXAMPLE 1.54
(RS)-N-(Ethoxycarbonyl)-S-methyl-S-[3-({[4-(thiazol-2-ylamino)quinazolin-7-
-yl]-amino}methyl)phenyl]sulphoximide
##STR00082##
[0637] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylam-
ino}phenyl)-N,N-dimethylformimidamide (90 mg, 0.21 mmol) with
2-aminothiazole (26 mg, 0.25 mmol) and chromatographic purification
(silica gel, dichloromethane/methanol: 0.fwdarw.30% methanol) gives
the desired product in 43% yield (43 mg).
[0638] .sup.1H-NMR (300 MHz, DMSO): .differential. 0.97 (t, 3H),
3.40 (s, 3H), 3.74-3.85 (m, 2H), 4.54 (d, 2H), 6.60 (d, 1H), 7.03
(dd, 1H), 7.17 (s, 1H), 7.41 (t, 1H), 7.47 (d, 1H), 7.62 (t, 1H),
7.72 (d, 1H), 7.80 (d, 1H), 7.95 (s, 1H), 8.35-8.48 (br, 2H), 11.71
(br, 1H).
EXAMPLE 1.55
(RS)-S-Methyl-S-[3-({[4-(thiazol-2-ylamino)quinazolin-7-yl]amino}methyl)-p-
henyl]sulphoximide
##STR00083##
[0640] According to GWP 6, the conversion of
(RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[4-(thiazol-2-ylamino)quinazolin--
7-yl]amino}methyl)phenyl]sulphoximide (40 mg, 0.083 mmol) and
chromatographic purification (silica gel, dichloromethane/methanol:
0.fwdarw.20% methanol) gives the desired product in 77% yield (26
mg).
[0641] .sup.1H-NMR (300 MHz, DMSO): .differential. 3.05 (s, 3H),
4.20 (s, 1H), 4.56 (d, 2H), 6.64 (d, 1H), 7.08 (dd, 1H), 7.22 (br,
1H), 7.45 (t, 1H), 7.52 (d, 1H), 7.59 (t, 1H), 7.68 (d, 1H), 7.99
(s, 1H), 8.40-8.53 (br, 2H), 11.81 (br, 1H).
EXAMPLE 1.56
(RS)-S-[3-({[6-Bromo-4-(isopropylamino)quinazolin-7-yl]amino}methyl)phenyl-
]-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00084##
[0643] 1.56.a) Preparation of the Intermediates
Compound 1.56.a.1
2-Amino-5-bromo-4-nitrobenzonitrile
##STR00085##
[0645] 2-Amino-4-nitrobenzonitrile (1.6 g, 9.81 mmol) is presented
as an initial charge in 30 mL of dioxane and is mixed at 10.degree.
C. with bromine (0.56 mL, 11 mmol). This is followed by stirring at
60.degree. C. for 6 hours. After cooling to room temperature, the
batch is added to dilute sodium thiosulphate solution. After
extraction of dichloromethane, the combined organic phases are
dried over sodium sulphate to leave, after removal of the solvent
and chromatographic purification (silica gel, n-hexane/ethyl
acetate: 0.fwdarw.100% ethyl acetate), the product in 36% yield
(820 mg).
[0646] .sup.1H-NMR (400 MHz, DMSO): .differential. 6.85 (s, 2H),
7.27 (s, 1H), 7.98 (s, 1H)
Compound 1.56.a.2
N'-(4-Bromo-2-cyano-5-nitrophenyl)-N,N-dimethylformimidamide
##STR00086##
[0648] 2-Amino-5-bromo-4-nitrobenzonitrile (815 mg, 3.37 mmol) is
admixed with N,N-dimethylformamide dimethyl acetal (1.65 mL, 12.5
mmol). After 20 minutes in an ultrasonic bath, excess
N,N-dimethylformamide dimethyl acetal is removed on a rotary
evaporator to leave, after chromatographic purification of the
residue (silica gel, n-hexane/ethyl acetate: 0.fwdarw.60% ethyl
acetate) the product in 86% yield (863 mg).
[0649] .sup.1H-NMR (400 MHz, DMSO): .differential. 2.99 (s, 3H),
3.07 (s, 3H), 7.83 (s, 1H), 8.14 (s, 1H), 8.16 (s, 1H).
Compound 1.56.a.3
[0650]
N'-(5-Amino-4-bromo-2-cyanophenyl)-N,N-dimethylformimidamide
##STR00087##
[0651] N'-(4-Bromo-2-cyano-5-nitrophenyl)-N,N-dimethylformimidamide
(1.1 g, 3.7 mmol) is dissolved in 500 mL of tetrahydrofuran, cooled
to 0.degree. C. and admixed with titanium trichloride solution (51
mL of a 15% solution in 10% aqueous HCl). This is followed by
stirring at room temperature for 4 hours. The batch is adjusted to
pH 9 at 0.degree. C. by means of 2N aqueous sodium hydroxide
solution. The mixture is diluted with water and ethyl acetate. The
aqueous phase is saturated with sodium chloride and stirred out
three times with ethyl acetate. The combined organic phases are
dried over sodium sulphate to leave, after removal of the solvent
and also chromatographic purification (silica gel, n-hexane/ethyl
acetate: 0.fwdarw.100% ethyl acetate, ethyl acetate/methanol 9/1),
the desired product in 60% yield (590 mg)
[0652] .sup.1H-NMR (300 MHz, DMSO): .differential. 2.89 (s, 3H),
2.99 (s, 3H), 5.93 (s, 2H), 6.27 (s, 1H), 7.52 (s, 1H), 7.68 (s,
1H).
[0653] 1.56.b) Preparation of the Final Product
[0654] N'-(5-Amino-4-bromo-2-cyanophenyl)-N,N-dimethylformimidamide
(580 mg, 2.17 mmol) is dissolved in 15 mL of dimethylformamide and
admixed with potassium carbonate (556 mg, 4.02 mmol) and also
(RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxy-carbonyl)-S-methylsulphoximide
(696 mg, 2.17 mmol). This is followed by 9 hours' stirring at
110.degree. C. After cooling to room temperature, the reaction
solution is diluted with ethyl acetate and the organic phase is
washed with water. Drying of the organic phase over sodium
sulphate, concentrating the solvent and chromatography (silica gel,
dichloromethane/methanol: 0.fwdarw.10% methanol) leaves 113 mg of
product which is reacted with isopropylamine (0.023 mL, 0.27 mmol)
according to GWP 5. Preparative thin layer chromatography gives the
desired product via 2 stages in 6% yield (63 mg).
[0655] .sup.1H-NMR (300 MHz, DMSO): .differential. 0.96 (t, 3H),
1.17 (d, 6H), 3.39 (s, 3H), 3.74-3.81 (m, 2H), 4.33-4.40 (m, 1H),
4.59 (d, 2H), 6.45 (s, 1H), 6.77 (t, 1H), 7.57-7.69 (m, 3H), 7.78
(d, 1H), 7.94 (s, 1H), 8.17 (s, 1H), 8.49 (s, 1H).
EXAMPLE 1.57
(RS)-S-[3-({[6-Bromo-4-(isopropylamino)quinazolin-7-yl]amino}methyl)phenyl-
]-S-methylsulphoximide
##STR00088##
[0657] According to GWP 6, the conversion of
(RS)-S-[3-({[6-bromo-4-(isopropylamino)-quinazolin-7-yl]amino}methyl)phen-
yl]-N-(ethoxycarbonyl)-S-methylsulphoximide (49 mg, 0.094 mmol) and
preparative thin layer chromatography (silica gel,
dichloromethane/methanol 9/1) gives the desired product in 85%
yield (36 mg).
[0658] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.17 (d, 6H),
2.99 (s, 3H), 4.15 (s, 1H), 4.33-4.40 (m, 1H), 4.57 (d, 1H), 6.44
(s, 1H), 6.74 (t, 1H), 7.49-7.63 (m, 3H), 7.76 (d, 1H), 7.93 (s,
1H), 8.16 (s, 1H), 8.49 (s, 1H).
EXAMPLE 1.58
(RS)-N-(Ethoxycarbonyl)-S-methyl-S-[3-({[4-(2-methyl-5-pyridylamino)-6-met-
hoxyquinazolin-7-yl]oxy}methyl)phenyl]sulphoximide
##STR00089##
[0660] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylox-
y}-4-methoxyphenyl)-N,N-dimethylformimidamide (100 mg, 0.22 mmol)
with 5-amino-2-methylpyridine (28 mg, 0.26 mmol) and chromatography
(silica gel, dichloromethane/methanol: 4/1) gives the desired
product in 36% yield (40 mg).
[0661] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.08 (t, 3H),
2.48 (s, 3H), 3.50 (s, 3H), 3.85-3.93 (m, 2H), 3.99 (s, 3H), 5.44
(s, 2H), 7.29 (d, 1H), 7.36 (s, 1H), 7.76 (t, 1H), 7.89-7.91 (m,
2H), 7.97 (d, 1H), 8.10-8.14 (m, 2H), 8.46 (s, 1H), 8.78 (d, 1H),
9.60 (s, 1H).
EXAMPLE 1.59
(RS)-S-[3-({[4-(2-Methyl-5-pyridylamino)-6-methoxyquinazolin-7-yl]oxy}meth-
yl)-phenyl]-S-methylsulphoximide
##STR00090##
[0663] According to GWP 6, the conversion of
(RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[4-(2-methyl-5-pyridylamino)-6-me-
thoxyquinazolin-7-yl]oxy}methyl)phenyl]-sulphoximide (33 mg, 0.063
mmol) and chromatography (silica gel, dichloromethane/methanol 4/1)
gives the desired product in 83% yield (24 mg).
[0664] .sup.1H-NMR (300 MHz, DMSO): .differential. 2.48 (s, 3H),
3.10 (s, 3H), 3.99 (s, 3H), 4.30 (s, 1H), 5.41 (s, 2H), 7.29 (d,
1H), 7.35 (s, 1H), 7.68 (t, 1H), 7.80 (d, H), 7.89 (s, 1H), 7.95
(d, 1H), 8.12 (dd, 1H), 8.46 (s, 1H), 8.78 (d, 1H), 9.60 (s,
1H).
EXAMPLE 1.60
(RS)-S-{3-[({4-[(3-Cyanophenyl)amino]-6-methoxyquinazolin-7-yl}oxy)methyl]-
-phenyl}-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00091##
[0666] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylox-
y}-4-methoxyphenyl)-N,N-dimethylformimidamide (100 mg, 0.22 mmol)
with 3-aminobenzonitrile (31 mg, 0.26 mmol) and chromatography
(silica gel, dichloromethane/methanol: 4/1) gives the desired
product in 71% yield (82 mg).
[0667] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.08 (t, 3H),
3.50 (s, 3H), 3.85-3.92 (m, 2H), 4.00 (s, 3H), 5.45 (s, 2H),
7.55-7.65 (m, 2H), 7.76 (t, 1H), 7.90-7.92 (m, 2H), 7.98 (d, 1H),
8.13-8.17 (m, 2H), 8.38 (s, 1H), 8.56 (s, 1H), 9.73 (s, 1H).
EXAMPLE 1.61
(RS)-S-{3-[({4-[(3-Cyanophenyl)amino]-6-methoxyquinazolin-7-yl}oxy)methyl]-
-phenyl}-S-methylsulphoximide
##STR00092##
[0669] According to GWP 6, the conversion of
(RS)-S-{3-[({4-[(3-cyanophenyl)amino]-6-methoxyquinazolin-7-yl}oxy)methyl-
]phenyl}-N-(ethoxycarbonyl)-S-methyl-sulphoximide (70 mg, 0.13
mmol) and chromatography (silica gel, dichloromethane/methanol 4/1)
gives the desired product in 79% yield (48 mg).
[0670] .sup.1H-NMR (400 MHz, DMSO): .differential. 3.05 (s, 3H),
3.96 (s, 3H), 4.25 (s, 1H), 5.38 (s, 2H), 7.34 (s, 1H), 7.51-7.65
(m, 3H), 7.75 (d, 1H), 7.84 (s, 1H), 7.90 (d, 1H), 8.06 (s, 1H),
8.11 (d, 1H), 8.34 (s, 1H), 8.52 (s, 1H), 9.68 (s, 1H).
EXAMPLE 1.62
(RS)-N-(Ethoxycarbonyl)-S-methyl-S-[3-({[4-(2-methyl-4-pyridylamino)-6-met-
hoxyquinazolin-7-yl]oxy}methyl)phenyl]sulphoximide
##STR00093##
[0672] According to GWP 5, the reaction of
N'-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylox-
y}-4-methoxyphenyl)-N,N-dimethylformimidamide (100 mg, 0.22 mmol)
with 4-amino-2-methylpyridine (28 mg, 0.26 mmol) and chromatography
(silica gel, dichloromethane/methanol: 4/1) gives the desired
product in 19% yield (21 mg).
[0673] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.03 (t, 3H),
2.43 (s, 3H), 3.45 (s, 3H), 3.81-3.88 (m, 2H), 3.97 (s, 3H), 5.41
(s, 2H), 7.37 (s, 1H), 7.70-7.79 (m, 3H), 7.85-7.87 (m, 2H), 7.92
(d, 1H), 8.09 (s, 1H), 8.32 (d, 1H), 8.59 (s, 1H), 9.61 (s,
1H).
EXAMPLE 1.63
(RS)-S-[3-({[4-(2-Methyl-4-pyridylamino)-6-methoxyquinazolin-7-yl]oxy}meth-
yl)-phenyl]-S-methylsulphoximide
##STR00094##
[0675] According to GWP 6, conversion of
(RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[4-(2-methyl-4-pyridylamino)-6-me-
thoxyquinazolin-7-yl]oxy}methyl)phenyl]-sulphoximide (20 mg, 0.038
mmol) and chromatography (silica gel, dichloromethane/methanol 4/1)
gives the desired product in 79% yield (14 mg).
[0676] .sup.1H-NMR (400 MHz, DMSO): .differential. 2,43 (s, 3H),
3.05 (s, 3H), 3.96 (s, 3H), 4.25 (s, 1H), 5.38 (s, 2H), 7.36 (s,
1H), 7.64 (t, 3H), 7.75-7.79 (m, 3H), 7.87 (s, 1H), 7.90 (d, 1H),
8.06 (s, 1H), 8.31 (d, 1H), 8.59 (s, 1H), 9.63 (s, 1H).
EXAMPLE 1.64
N-{2-[(6-Bromo-7-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]-benzy-
loxy}quinazolin-4-yl)amino]ethyl}acetamide
##STR00095##
[0678] According to GWP 5,
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethylformimidamide (70 mg, 0.14
mmol) is reacted with N-(2-aminoethyl)acetamide (0.02 mL mg, 0.17
mmol). The reaction solution is admixed with dilute sodium
bicarbonate solution and the resulting crystals are filtered off
with suction to obtain the desired product in 76% yield (59
mg).
[0679] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.02 (t, 3H),
1.77 (s, 3H), 3.25-3.29 (m, 2H+water), 3.44 (s, 3H), 3.48-3.54 (m,
2H), 3.80-3.91 (m, 2H), 5.46 (s, 2H), 7.31 (s, 1H), 7.72 (t, 1H),
7.85 (d, 1H), 7.91 (d, 1H), 7.98 (t, 1H), 8.10 (s, 1H), 8.31 (t,
1H), 8.40 (s, 1H), 8.56 (s, 1H).
EXAMPLE 1.65
N-{2-[(6-Bromo-7-{3-[(RS)-S-methylsulphonimidoyl]benzyloxy}quinazolin-4-yl-
)-amino]ethyl}acetamide
##STR00096##
[0681] According to GWP 6, the conversion of
N-{2-[(6-bromo-7-{3-[(RS)-N-(ethoxy-carbonyl)-S-methylsulphonimidoyl]benz-
yloxy}quinazolin-4-yl)amino]ethyl}acetamide (86 mg, 0.15 mmol) and
chromatography (silica gel, dichloromethane/methanol: 0.fwdarw.10%
methanol) gives the desired product in 45% yield (33 mg).
[0682] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.77 (s, 3H),
3.04 (s, 3H), 3.23-3.29 (m, 2H+water), 3.47-3.54 (m, 2H), 4.24 (s,
1H), 5.43 (s, 2H), 7.30 (s, 1H), 7.63 (t, 1H), 7.76 (d, 1H), 7.89
(d, 1H), 7.98 (t, 1H), 8.07 (s, 1H), 8.30 (t, 1H), 8.39 (s, 1H),
8.56 (s, 1H).
EXAMPLE 1.66
(RS)-S-[3-({[6-Bromo-4-(ethylamino)quinazolin-7-yl]oxy}methyl)phenyl]-N-(e-
thoxycarbonyl)-S-methylsulphoximide
##STR00097##
[0684] According to GWP 5, the reaction of
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxy-carbonyl)-S-methylsulphoni-
midoyl]benzyloxy}phenyl)-N,N-dimethylformimidamide (70 mg, 0.14
mmol) with ethylamine (0.08 mL mg, 0.17 mmol) and thin layer
chromatography (silica gel, dichloromethane/methanol: 9/1) gives
the desired product in 71% yield (50 mg)
[0685] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.02 (t, 3H),
1.18 (t, 3H), 3.44 (s, 3H), 3.47-3.53 (m, 2H), 3.80-3.91 (m, 2H),
5.45 (s, 2H)7.29 (s, 1H), 7.72 (t, 1H), 7.85 (d, 2H), 7.91 (d, 1H),
8.11 (s, 1H), 8.19 (t, 1H), 8.39 (s, 1H), 8.59 (s, 1H).
EXAMPLE 1.67
(RS)-S-[3-({[6-Bromo-4-(ethylamino)quinazolin-7-yl]oxy}methyl)phenyl]-S-me-
thylsulphoximide
##STR00098##
[0687] According to GWP 6,
(RS)-S-[3-({[6-bromo-4-(ethylamino)quinazolin-7-yl]oxy}methyl)-phenyl]-N--
(ethoxycarbonyl)-S-methylsulphoximide (38 mg, 0.075 mmol) is
dissolved in ethanol (5 mL), admixed with sodium ethoxide (19 mg,
0.27 mmol) and stirred at 60.degree. C. for 3 hours. The reaction
solution is admixed with saturated sodium bicarbonate solution and
extracted with ethyl acetate. After drying of the organic phase
over sodium sulphate and removal of the solvent, the residue is
subsequently stirred up with methanol and the crystals are filtered
off with suction to obtain the desired product in 45% yield (33
mg).
[0688] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.18 (s, 3H),
3.04 (s, 3H), 3.46-3.52 (m, 2H), 4.23 (s, 1H), 5.43 (s, 2H), 7.29
(s, 1H), 7.64 (t, 1H), 7.76 (d, 1H), 7.88 (d, 1H), 8.08 (s, 1H),
8.19 (t, 1H), 8.38 (s, 1H), 8.58 (s, 1H).
EXAMPLE 1.68
(RS)-S-{3-[({6-Bromo-4-[(3-hydroxy-2,2-dimethylpropyl)amino]quinazolin-7-y-
l}-oxy)methyl]phenyl}-S-methylsulphoximide
##STR00099##
[0690] According to GWP 5,
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethylformimidamide (75 mg, 0.15
mmol) is reacted with 3-amino-2,2-dimethyl-1-propanol (18 mg, 0.18
mmol). After the reaction has ended, the reaction solution is
diluted with dilute sodium bicarbonate solution and subsequently
extracted with ethyl acetate. Drying of the organic phase over
sodium sulphate, removal of the solvent and chromatographic
purification of the residue (silica gel, dichloromethane/methanol:
0.fwdarw.10% methanol) gives 67 mg of product which is subsequently
reacted with sodium ethoxide (29 mg, 0.41 mmol) according to GWP 6.
Chromatographic purification (silica gel, dichloromethane/methanol:
0.fwdarw.10% methanol) gives via 2 stages the desired product in
35% yield (26 mg).
[0691] .sup.1H-NMR (300 MHz, DMSO): .differential. 0.80 (s, 6H),
3.04 (s, 3H), 3.10 (d, 2H), 3,86 (s, 2H), 4.24 (s, 1H), 4.81 (t,
1H), 5.46 (s, 2H), 7.35 (s, 1H), 7.64 (t, 1H), 7.75 (d, 1H), 7.89
(d, 1H), 8.07 (s, 1H), 8.24-8.26 (m, 2H).
EXAMPLE 1.69
(RS)-S-(3-{[(6-Bromo-4-{[(RS)-2-hydroxy-1-methylethyl]amino}quinazolin-7-y-
l)-oxy]methyl}phenyl)-S-methylsulphoximide
##STR00100##
[0693] According to GWP 5,
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethylformimidamide (250 mg, 0.49
mmol) is reacted with alaninol (0.05 mL, 0.59 mmol). After the
reaction has ended, the reaction solution is diluted with dilute
sodium bicarbonate solution and subsequently extracted with ethyl
acetate. Drying of the organic phase over sodium sulphate, removal
of the solvent and chromatographic purification of the residue
(silica gel, dichloromethane/methanol: 0.fwdarw.10% methanol)
leaves 146 mg of product which is subsequently reacted with sodium
ethoxide (67 mg, 0.98 mmol) according to GWP 6. Chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.10%
methanol) gives via 2 stages the desired product in 26% yield (59
mg).
[0694] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.35 (d, 3H),
3.04 (s, 3H), 3.55-3.62 (m,1 H), 3.67-3.75 (m, 1H), 4.23 (s, 1H),
4.76-4.82 (m, 1H), 4.99 (t, 1H), 5.46 (s, 2H), 7.35 (s, 1H), 7.63
(t, 1H), 7.75 (d, 1H), 7.88 (d, 1H), 8.08 (s, 1H), 8.24 (s, 1H),
8.35 (s, 1H).
EXAMPLE 1.70
(RS)-S-(3-{[(6-Bromo-4-{[(S)-2-hydroxypropyl]amino}quinazolin-7-yl)oxy]-me-
thyl}phenyl)-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00101##
[0696] According to GWP 5,
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethylformimidamide (80 mg, 0.16
mmol) is reacted with (S)-1-amino-2-propanol (14 mg, 0.19 mmol).
After the reaction has ended, the reaction solution is diluted with
dilute sodium bicarbonate solution and the resulting precipitate is
filtered off with suction. Chromatographic purification of the
residue (silica gel, dichloromethane/methanol: 0.fwdarw.10%
methanol) gives the desired product in 58% yield (49 mg).
[0697] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.06 (t, 3H),
1.10 (d, 3H), 3.37-3.50 (m, 5H), 3.84-3.94 (m, 3H), 4.84 (d, 1H),
5.50 (s, 2H), 7.34 (s, 1H), 7.76 (t, 1H), 7.90 (d, 1H), 7.95 (d,
1H), 8.15 (s, 1H), 8.29 (t, 1H), 8.42 (s, 1H), 8.70 (s, 1H).
EXAMPLE 1.71
(RS)-S-(3-{[(6-Bromo-4-{[(S)-2-hydroxypropyl]amino}quinazolin-7-yl)oxy]-me-
thyl}phenyl)-S-methylsulphoximide
##STR00102##
[0699] According to GWP 6,
(RS)-S-(3-{[(6-bromo-4-{[(S)-2-hydroxypropyl]amino}quinazolin-7-yl)oxy]me-
thyl}phenyl)-N-(ethoxycarbonyl)-S-methylsulphoximide (39 mg, 0.073
mmol) is dissolved in ethanol (5 mL), admixed with sodium ethoxide
(18 mg, 0.26 mmol) and stirred at 60.degree. C. for 6 hours. The
reaction solution is admixed with saturated sodium bicarbonate
solution and extracted with ethyl acetate. Drying of the organic
phase over sodium sulphate and removal of the solvent and also
chromatographic purification of the residue (silica gel,
dichloromethane/methanol: 0.fwdarw.10% methanol) gives the desired
product in 86% yield (29 mg).
[0700] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.06 (d, 3H),
3.04 (s, 3H), 3.38-3.45 (m, 2H), 3.89 (br, 1H), 4.25 (br, 1H), 4.79
(d, 1H), 5.43 (s, 2H), 7.29 (s, 1H), 7.64 (t, 1H), 7.76 (d, 1H),
7.88 (d, 1H), 8.08 (s, 1H), 8.24 (t, 1H), 8.37 (s, 1H), 8.65 (s,
1H).
EXAMPLE 1.72
(RS)-S-(3-{[(6-Bromo-4-{[(R)-2-hydroxypropyl]amino}quinazolin-7-yl)oxy]-me-
thyl}-phenyl)-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00103##
[0702] According to GWP 5,
(E/Z)-N'-(4-bromo-2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonim-
idoyl]benzyloxy}phenyl)-N,N-dimethylformimidamide (80 mg, 0.16
mmol) is reacted with (R)-1-amino-2-propanol (14 mg, 0.19 mmol).
After the reaction has ended, the reaction solution is diluted with
dilute sodium bicarbonate solution and the resulting precipitate is
filtered off with suction. Chromatographic purification of the
precipitate (silica gel, dichloromethane/methanol: 0.fwdarw.10%
methanol) gives the desired product in 58% yield (49 mg).
[0703] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.06 (t, 3H),
1.10 (d, 3H), 3.39-3.50 (m, 5H), 3.84-3.94 (m, 3H), 4.84 (d, 1H),
5.50 (s, 2H), 7.34 (s, 1H), 7.76 (t, 1H), 7.89 (d, 1H), 7.95 (d,
1H), 8.15 (s, 1H), 8.29 (t, 1H), 8.42 (s, 1H), 8.70 (s, 1H).
EXAMPLE 1.73
(RS)-S-(3-{[(6-Bromo-4-{[(R)-2-hydroxypropyl]amino}quinazolin-7-yl)oxy]-me-
thyl}phenyl)-S-methylsulphoximide
##STR00104##
[0705] According to GWP 6,
(RS)-S-(3-{[(6-bromo-4-{[(R)-2-hydroxypropyl]amino}quinazolin-7-yl)oxy]me-
thyl}phenyl)-N-(ethoxycarbonyl)-S-methylsulphoximide (38 mg, 0.071
mmol) is dissolved in ethanol (5 mL), admixed with sodium ethoxide
(17 mg, 0.25 mmol) and stirred at 60.degree. C. for 6 hours. The
reaction solution is admixed with saturated sodium bicarbonate
solution and extracted with ethyl acetate. Drying of the organic
phase over sodium sulphate and removal of the solvent and also
chromatographic purification of the residue (silica gel,
dichloromethane/methanol: 0.fwdarw.10% methanol) gives the desired
product in 88% yield (29 mg).
[0706] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.06 (d, 3H),
3.04 (s, 3H), 3.36-3.48 (m, 2H), 3.89 (br, 1H), 4.25 (br, 1H), 4.79
(d, 1H), 5.43 (s, 2H), 7.29 (s, 1H), 7.64 (t, 1H), 7.76 (d, 1H),
7.89 (d, 1H), 8.08 (s, 1H), 8.24 (t, 1H), 8.37 (s, 1H), 8.65 (s,
1H).
[0707] 2. Process Variant 2
EXAMPLE 2.1
(RS)-N-(Ethoxycarbonyl)-S-[3-({[4-(isopropylamino)quinazolin-7-yl]oxy}meth-
yl)-phenyl]-S-methylsulphoximide
##STR00105##
[0709] 2.1.a) Preparation of the Intermediates
Compound 2.1.a.1
4-Amino-5-cyano-2-hydroxybenzoic acid
##STR00106##
[0711] Ethyl 4-amino-5-cyano-2-hydroxybenzoate (3 g, 14.55 mmol) is
treated with 60 ml of a 10% strength sodium hydroxide solution and
the mixture is stirred at 50.degree. C. for one hour. After
cooling, the reaction solution is acidified with concentrated
hydrochloric acid, diluted with water and the precipitate is
filtered off with suction. The desired product is obtained after
recrystallization from ethanol in 62% yield (1.6 g).
[0712] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 6.17 (s, 1H), 6.73
(brs, 2H), 7.86 (s, 1H), 11.71 (br s, 1 H), 13.62 (br s,1 H).
Compound 2.1 a.2
2-Amino-4-hydroxybenzonitrile
##STR00107##
[0714] 4-Amino-5-cyano-2-hydroxybenzoic acid (2.1 g, 11.79 mmol) is
added to a quinoline solution already heated to 160.degree. C. (12
ml) and the reaction solution is stirred at 180.degree. C. for a
further hour. After cooling, it is diluted with about 50 ml of a 1N
sodium hydroxide solution. The mixture is extracted with
dichloromethane. Subsequently, the aqueous phase is adjusted to pH
6.5 with hydrochloric acid and extracted with ethyl acetate and
methanol (as a solubilizer). The combined organic phases are dried
over sodium sulphate. The desired product is obtained after
concentrating the solvents in 76% yield (1.2 g).
[0715] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 5.81 (s, 2H), 6.04
(dd, 1H), 6.16 (d, 1H), 7.17 (d, 1H), 9.98 (s, 1H).
Compound 2.1.a.3
(E/Z)-N'-(2-Cyano-5-hydroxyphenyl)-N,N-dimethylformimidamide
##STR00108##
[0717] 2-Amino-4-hydroxybenzonitrile (1.1 g, 8.2 mmol) and
dimethylformamide dimethyl acetal (3.91 g, 33 mmol) are combined
and stirred at room temperature for 2 hours. The reaction solution
is concentrated. The desired product is obtained after
chromatographic purification (silica gel, dichloromethane/methanol:
9/1) of the residue in 86% yield (1.4 g)
[0718] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 2.95 (s, 3H), 3.05
(s, 3H), 6.41-6.46 (m, 2H), 7.38 (d, 1H), 7.82 (s, 1H), 10.17 (s,
1H).
Compound 2.1.a.4 4-(Isopropylamino)quinazolin-7-ol
##STR00109##
[0720] According to GWP 5,
(E/Z)-N'-(2-cyano-5-hydroxyphenyl)-N,N-dimethylformimid-amide (1.4
g, 7.4 mmol) is reacted in 2 portions with isopropylamine (0.53 g,
8.88 mmol) in acetonitrile (14 ml) and acetic acid (7 ml). The
reaction solution is concentrated and the residue is triturated
with diethyl ether. The crystals are filtered off with suction and
dried. The desired product is obtained in quantitative yield (2.1
g).
[0721] LC-MS (Instrument: Micromass Platform LCZ with HPLC Agilent
Series 1100; column: Thermo Hypersil GOLD 3.mu. 20.times.4 mm;
eluent A: 1 l of water+0.5ml of 50% strength formic acid, eluent B:
1 l of acetonitrile+0.5 ml 50% of strength formic acid; gradient:
0.0 min 100% A.fwdarw.0.2 min 100% A.fwdarw.2.9 min 30%
A.fwdarw.3.1min 10% A.fwdarw.5.5 min 10% A; oven:50.degree. C.;
flow: 0.8 ml/min; UV detection: 210 nm):R.sub.t=2.16 min; MS (ESI
pos.): m/z=204 (M+H.sup.+).
[0722] 2.1.b) Preparation of the Final Product
[0723] 4-(Isopropylamino)quinazolin-7-ol (60 mg, 0.23 mmol) and
(RS)-S-[3-(bromomethyl)-phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide
(112 mg, 0.29 mmol) are suspended in 10 ml of acetone. After
addition of caesium carbonate (264 mg, 0.81 mmol), the reaction
mixture is refluxed for 4 hours. The batch is diluted with ethyl
acetate, and the organic phase is washed with water and dried over
sodium sulphate. The desired product is obtained after removing the
solvent and after chromatographic purification (silica gel,
dichloromethane/methanol: 9/1), in 62% yield (70 mg).
[0724] LC-MS (method: see Example 1.16):R.sub.t=1.00 min; MS (ESI
pos.): m/z=443 (M+H.sup.+).
EXAMPLE 2.2
(RS)-S-[3-({[4-(Isopropylamino)quinazolin-7-yl]oxy}methyl)phenyl]-S-methyl-
-sulphoximide
##STR00110##
[0726] According to GWP 6,
(RS)-N-(ethoxycarbonyl)-S-[3-({[4(isopropylamino)quinazolin-7-yl]oxy}meth-
yl)phenyl]-S-methylsulphoximide (68 mg, 0.16 mmol) is reacted with
sodium ethoxide (46 mg, 0.68 mmol) at 80.degree. C. for 2 hours.
The reaction mixture is concentrated to dryness. The residue is
taken up in ethyl acetate and water. The organic phase is separated
off, dried over sodium sulphate and subsequently concentrated. The
residue is triturated a number of times with diethyl ether and the
solvent is subsequently decanted off. The residue is dissolved in
dichloromethane and concentrated again. The desired product is
obtained in 51% yield (30 mg).
[0727] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.24 (d, 6H), 3.08
(s, 3H), 4.26 (s, 1H), 4.48 (dsept, 1H), 5.36 (s, 2H), 7.18 (d,
1H), 7.20 (dd, 1H), 7.65 (t, 1H), 7.74-7.79 (m, 2H), 7.91 (d, 1H),
8.08 (s, 1H), 8.25 (d, 1H), 8.38 (s, 1H).
EXAMPLE 2.3
Ethyl
7-({(RS)-3-[N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyl}oxy)-4--
(thiazol-2-ylamino)quinazoline-6-carboxylate
##STR00111##
[0728] 2.3.a) Preparation of the Intermediate
[0729] Ethyl
7-hydroxy-4-(thiazol-2-ylamino)quinazoline-6-carboxylate,
acetate
##STR00112##
[0730] According to GWP 5,
ethyl-5-cyano-4-{(E/Z)-[(dimethylamino)methylene]amino}-2-hydroxybenzoate
(2.0 g, 7.7 mmol) is reacted with 2-aminothiazole (0.92 g, 9.18
mmol) in acetonitrile (10 ml) and acetic acid (5 ml). After
cooling, the resulting crystals are stirred with diethyl ether,
filtered off with suction and dried. The desired product is
obtained in 73% yield (2.1 g) as the acetic acid salt.
[0731] LC-MS (method: see Example 1.16):R.sub.t=1.08 min. MS (ESI
pos.): m/z=317 (M+H.sup.+).
[0732] 2.3.b) Preparation of the Final Product
[0733] Ethyl
7-hydroxy-4-(thiazol-2-ylamino)quinazoline-6-carboxylate, acetate
(80 mg, 0.213 mmol) and
(RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-methyl-sulphoximide
(104 mg, 0.28 mmol) are suspended in 10 ml of acetone. After the
addition of caesium carbonate (264 mg, 0.81 mmol), the reaction
mixture is initially refluxed for 4 hours, N,N-dimethylformamide (3
ml) is added and it is stirred and refluxed for a further 3 hours.
After cooling, the batch is concentrated, the residue is taken up
in ethyl acetate and water, and the organic phase is separated off
and dried over sodium sulphate. After removing the solvent, the
residue (175 mg, 86% of theory) is employed in the next reaction
without further purification.
[0734] LC-MS (apparatus type MS: Micromass ZQ; apparatus type HPLC:
HP 1100 Series; UV DAD; column: Phenomenex Gemini 3.mu. 30
mm.times.3.00 mm; eluent A: 1 l of water+0.5 ml of 50% strength
formic acid, eluent B: 1 l of acetonitrile+0.5 ml of 50% strength
formic acid; gradient: 0.0 min 90% A.fwdarw.2.5 min 30%
A.fwdarw.3.0 min 5% A.fwdarw.4.5 min 5% A; flow: 0.0 min 1 ml/min,
2.5 min/3.0 min/4.5 min. 2 ml/min; oven: 50.degree. C.; UV
detection: 210 nm):R.sub.t=1.68 min; MS (ESI pos.): m/z=556
(M+H.sup.+).
EXAMPLE 2.4
Ethyl
7-{[(RS)-3-(S-methylsulphonimidoyl)benzyl]oxy}-4-(thiazol-2-ylamino)-
-quinazoline-6-carboxylate
##STR00113##
[0736] According to GWP 6,
ethyl-7-({(RS)-3-[N-(ethoxycarbonyl)-S-methyl-sulphonimidoyl]-benzyl}oxy)-
-4-(thiazol-2-ylamino)quinazoline-6-carboxylate (175 mg, 0.182
mmol) is reacted at 80.degree. C. for 2 hours with sodium ethoxide
(55 mg, 0.8 mmol). After cooling, the reaction mixture is
concentrated to dryness. The residue is taken up in ethyl acetate
and water. The organic phase is separated off, dried over sodium
sulphate and subsequently concentrated. The desired product is
obtained after chromatographic purification (silica gel,
dichloromethane/methanol: 9/1) in 42% yield (39 mg).
[0737] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.38 (t, 3H), 2.99
(s, 3H), 4.18 (s, 1H), 4.43 (q, 2H), 5.57 (s, 2H), 7.13 (s, 1H),
7.18 (d, 1H), 7.61 (t, 1H), 7.80 (d, 1H), 7.87 (d, 2H), 8.01 (s,
1H), 8.76 (s, 1H), 9.02 (s, 1H), 10.86 (s, 1H).
EXAMPLE 2.5
(RS)-N-(Ethoxycarbonyl)-S-[3-({[4-(isopropylamino)-6-methoxyquinazolin-7-y-
l]oxy}methyl)phenyl]-S-methylsulphoximide
##STR00114##
[0739] 2.5.a) Preparation of the Intermediate
4-(Isopropylamino)-6-methoxyquinazolin-7-ol
##STR00115##
[0741] According to GWP 5,
(E/Z)-N'-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethyl-formimidamide
(0.62 g, 2.25 mmol) prepared according to WO2004/58752 is reacted
with isopropylamine (0.16 g, 2.7 mmol) in acetonitrile (3 ml) and
acetic acid (0.7 ml). After cooling, the batch is rendered alkaline
by means of saturated sodium hydrogencarbonate solution and
extracted with ethyl acetate. Concentrating the organic phase, the
desired product is obtained in 55% yield (310 mg) as the acetic
acid salt.
[0742] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.26 (d, 6H), 3.91
(s, 3H), 4.49 (dsept, 1H), 6.94 (s, 1H), 7.45 (d, 1H), 7.59 (s,
1H), 8.25 (s, 1H), 10.08 (br s, 1H).
[0743] 2.5.b) Preparation of the Final Product
[0744] 4-(Isopropylamino)-6-methoxyquinazolin-7-ol (65 mg, 0.21
mmol) and
(RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide
(102 mg, 0.27 mmol) are suspended in 14 ml of acetone. After
addition of caesium carbonate (2427 mg, 0.74 mmol), the reaction
mixture is stirred at reflux for 3 hours. After cooling, the batch
is concentrated, the residue is taken up in ethyl acetate, and the
organic phase is washed with water and dried over sodium sulphate.
After removal of the solvent, the residue (144 mg, 97% of theory)
is employed in the next reaction without further purification.
[0745] LC-MS (method see Compound 1.16.a.3):R.sub.t=1.19 min; MS
(ESI pos.): m/z=473 (M+H.sup.+).
EXAMPLE 2.6
(RS)-S-[3-({[4-(Isopropylamino)-6-methoxyquinazolin-7-yl]oxy}methyl)phenyl-
]-S-methylsulphoximide
##STR00116##
[0747]
(RS)-N-(Ethoxycarbonyl)-S-[3-({[4-(isopropylamino)-6-methoxyquinazo-
lin-7-yl]oxy}-methyl)phenyl]-S-methylsulphoximide (105 mg, 0.22
mmol) is introduced into 2.5 ml of ethanol. 1.0 ml of a 1-molar
ethanolic sodium ethoxide solution is added and the mixture is
heated to 80.degree. C., until starting material is no longer
present according to TLC checking (eluent dichloromethane/methanol
10:1). The reaction solution is concentrated in vacuo, and the
residue is taken up in ethyl acetate and washed with saturated
sodium carbonate solution. The organic phase is dried over sodium
sulphate and concentrated. The crude product is purified by
preparative HPLC and the desired product is obtained in 36% yield
(32 mg).
[0748] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.27 (d, 6H), 3.08
(s, 3H), 3.92 (s, 3H), 4.27 (s, 1H), 4.50 (dsept, 1H), 5.35 (s,
2H), 7.20 (s, 1H), 7.56 (d, 1H), 7.63-7.68 (m, 2H), 7.77 (d, 1H),
7.92 (d, 1H), 8.07 (s, 1H), 8.32 (s, 1H).
EXAMPLE 2.7
(RS)-S-[4-({[6-Bromo-4-(isopropylamino)quinazolin-7-yl]oxy}methyl)phenyl]--
N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00117##
[0750] 2.7.a) Preparation of the Intermediates
Compound 2.7.a.1
(RS)-S-Methyl-S-(m-tolyl)sulphoximide
##STR00118##
[0752] According to GWP 2, in the case of the reaction of
4-methylphenylsulphinyl (1.0 g, 6.5 mmol), the desired product is
obtained after chromatographic purification (silica gel,
hexane/ethyl acetate: 0.fwdarw.100% ethyl acetate, then ethyl
acetate/methanol: 9/1) in 93% yield (1.02 g).
[0753] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 2.35 (s, 3H), 2.98
(s, 3H), 4.97 (s, 1H), 7.36 (d, 2H), 7.77 (d, 2H).
Compound 2.7.a.2
(RS)-N-(Ethoxycarbonyl)-S-methyl-S-(p-tolyl)sulphoximide
##STR00119##
[0755] According to GWP 3, in the case of the reaction of
(RS)-S-methyl-S-(m-tolyl)-sulphoximide (1.02 g, 6.03 mmol), the
desired product is obtained after chromatographic purification
(silica gel, hexane/ethyl acetate: 0.fwdarw.100% ethyl acetate,
then ethyl acetate/methanol: 9/1) in 96% yield (1.39 g).
[0756] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 1,05 (t, 3H), 2.38
(s, 3H), 3.39 (s, 3H), 3.82-3.92 (m, 2H), 7.45 (d, 2H), 7.79 (d,
2H).
Compound 2.7.a.3
(RS)-S-[4-(Bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00120##
[0758] According to GWP 4, in the case of the reaction of
(RS)-N-(ethoxycarbonyl)-S-methyl-S-(p-tolyl)sulphoximide (0.5 g,
2.07 mmol), the desired product is obtained after chromatographic
purification (silica gel, hexane/ethyl acetate: 0.fwdarw.100% ethyl
acetate, then ethyl acetate/methanol: 4/1) in 65% yield (0.43
g).
[0759] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1,04 (t, 3H), 3.43
(s, 3H), 3.82-3.91 (m, 2H), 4.77 (s, 2H), 7.70 (d, 2H), 7.90 (d,
2H).
Compound 2.7.a.4
6-Bromo-7-methoxy-3H-quinazolin-4-one
##STR00121##
[0761] 2-Amino-5-bromo-4-methoxybenzoic acid (1.56 g, 6.34 mmol) is
dissolved in methanol (15 ml), treated with piperidine (0.063 ml,
0.63 mmol) and 1,3,5-triazine (772 mg, 9.5 mmol) and refluxed for
one hour. After cooling to room temperature, the resulting crystals
are filtered off with suction and washed with methanol. The desired
product is obtained in 63% yield (1.01 g).
[0762] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 3.95 (s, 3H), 7.20
(s, 1H), 8.08 (s, 1H), 8.16 (s, 1H), 12.2 (br, 1H).
Compound 2.7.a.5
(6-Bromo-4-methoxyquinazolin-4-yl)isopropylamine
##STR00122##
[0764] 6-Bromo-7-methoxy-3H-quinazolin-4-one (1.01 g, 3.96 mmol)
and N,N-(diisopropyl-ethylamine (1.78 ml, 10.4 mmol) are introduced
into 1,2-dichloroethane (19 ml), treated dropwise with POCl.sub.3
(0.46 ml, 4.95 mmol) and then stirred at 80.degree. C. for 2 h. The
reaction mixture is subsequently concentrated to dryness. The
residue is taken up in isopropanol (10 ml), treated with
isopropylamine (0.34 ml, 3.96 mmol) and stirred for 30 minutes at
80.degree. C. After cooling to room temperature, the resulting
precipitate is filtered off with suction and dried in vacuo. The
desired product is obtained in 46% yield (530 mg).
[0765] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.20 (d, 6H), 3.93
(s, 3H), 4.38-4.46 (m, 1H), 7.14 (s, 1H), 7.87 (d, 1H), 8.38 (s,
1H), 8.63 (s, 1H).
Compound 2.7.a.6
6-Bromo-4-(isopropylamino)quinazolin-7-ol
##STR00123##
[0767] (6-Bromo-4-methoxyquinazolin-4-yl)isopropylamine (430 mg,
1.45 mmol) is introduced into CH.sub.2Cl.sub.2 (15 ml), a 1M boron
tribromide solution (30 ml) in methylene chloride is added dropwise
at room temperature and the mixture is stirred at RT for 20 hours.
The reaction is terminated by addition of methanol. After removal
of the solvent, the residue is treated with triethylamine and
concentrated again. The desired product is obtained after
chromatographic purification (silica gel, dichloromethane/methanol:
0.fwdarw.20% methanol), in 12% yield (50 mg).
[0768] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 1.23 (d, 6H),
4.48-4.57 (m, 1H), 7.13 (s, 1H), 8.56 (s, 1H), 8.71 (s, 1H).
[0769] 2.7.b) Preparation of the Final Product
[0770] 6-Bromo-4-(isopropylamino)quinazolin-7-ol (50 mg, 0.18 mmol)
and
(RS)-S-[4-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide
(86 mg, 0.27 mmol) are suspended in acetone (10 ml), treated with
potassium carbonate (45 mg, 0.33 mmol) and refluxed for 6 hours.
After cooling, the batch is diluted with ethyl acetate and washed
with water. The organic phase is dried over sodium sulphate and
subsequently concentrated. The desired product is obtained after
chromatographic purification (silica gel, dichloromethane/methanol:
0.fwdarw.20% methanol), in 45% yield (42 mg).
[0771] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 1.09 (t, 3H), 1.25
(d, 6H), 3.49 (s, 3H), 3.86-3.97 (m, 2H), 4.41-4.53 (m, 1H), 5.52
(s, 2H), 7.31 (s, 1H), 7.82 (d, 2H), 7.94 (d, 1H), 8.03 (d, 2H),
8.42 (s, 1H), 8.72 (s, 1H).
Example 2.8
(RS)-S-[4-({[6-Bromo-4-(isopropylamino)quinazolin-7-yl]oxy}methyl)phenyl]--
S-methylsulphoximide
##STR00124##
[0773]
(RS)-S-[4-({[6-Bromo-4-(isopropylamino)quinazolin-7-yl]oxy}methyl)p-
henyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (37 mg, 0.07 mmol)
is dissolved in ethanol (5 ml), treated with sodium ethoxide (16
mg, 0.26 mmol), and is stirred at 60.degree. C. for 6 hours and
subsequently stirred at room temperature overnight. The batch is
added to dilute aqueous sodium carbonate solution and extracted
with ethyl acetate. The combined organic phases are dried over
sodium sulphate and concentrated. The desired product is obtained
after chromatographic purification (silica gel,
dichloro-methane/methanol: 020% methanol) of the residue in 79%
yield (25 mg)
[0774] .sup.1H-NMR (300 MHz, DMSO-d6): .delta. 1.20 (d, 6H), 3.04
(s, 3H), 4.25-4.48 (m, 2H), 5.44 (s, 2H), 7.24 (s, 1H), 7.68 (d,
2H), 7.91-7.96 (m, 3H), 8.38 (s, 1H), 8.67 (s, 1H).
EXAMPLE 2.9
(RS)-N-(Ethoxycarbonyl)-S-ethyl-S-[3-({[4-(isopropylamino)-6-methoxy-quina-
zolin-7-yl]oxy}methyl)phenyl]sulphoximide
##STR00125##
[0776] 4-(Isopropylamino)-6-methoxyquinazolin-7-ol (50 mg, 0.21
mmol) and
(RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide
(108 mg, 0.32 mmol) are suspended in 5.0 mL of acetone. After
addition of potassium carbonate (55 mg, 0.4 mmol), the reaction
mixture is refluxed for 6 hours. The batch is diluted with ethyl
acetate and the organic phase is washed with water and dried over
sodium sulphate to leave, after removal of the solvent and also
after chromatographic purification (silica gel, hexane/ethyl
acetate: 0.fwdarw.100% ethyl acetate, followed by ethyl
acetate/methanol: 9/1) the desired product in 62% yield (65
mg).
[0777] .sup.1H-NMR (300 MHz, DMSO): .differential. 0.99-1.07 (m,
6H), 1.23 (d, 6H), 3.47-3.60 (m, 2H), 3.76-3.90 (m, 5H), 4.43-4.49
(m, 1H), 5.35 (s, 2H), 7.16 (s, 1H), 7.54 (d, 1H), 7.62 (s, 1H),
7.70 (t, 1H), 7.82-7.85 (m, 2H, 7.99 (s, 1H), 8.28 (s, 1H).
EXAMPLE 2.10
(RS)-S-Ethyl-S-[3-({[4-(isopropylamino)-6-methoxyquinazolin-7-yl]oxy}-meth-
yl)phenyl]sulphoximide
##STR00126##
[0779] According to GWP 6, the conversion of
(RS)-N-(ethoxycarbonyl)-S-ethyl-S-[3-({[4-(isopropylamino)-6-methoxyquina-
zolin-7-yl]oxy}methyl)phenyl]sulphoximide (64 mg, 0.13 mmol) and
chromatographic purification (silica gel, hexane, ethyl
acetate/methanol: 0.fwdarw.10% methanol, followed by
dichloromethane/methanol: 0.fwdarw.15% methanol) gives the desired
product in 82% yield (45 mg).
[0780] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.01 (t, 3H),
1.23 (d, 6H), 3.08 (q, 2H), 3.88 (s, 3H), 4.19 (s, 1H), 4.42-4.49
(m, 1H), 5.32 (s, 2H), 7.15 (s, 1H), 7.54 (d, 1H), 7.59-7.64 (m,
2H), 7.73 (d, 1H), 7.81-7.83 (d, 1H), 7.97 (s, 1H), 8.28 (s,
1H).
EXAMPLE 2.11
(RS)-S-[3-({[6-Cyano-4-(isopropylamino)quinazolin-7-yl]oxy}methyl)phenyl]--
N-(ethoxycarbonyl)-S-methylsulphoximide
##STR00127##
[0782] 2.11.a) Preparation of the Intermediates
Compound 2.11.a.1
6-(Hydroxymethyl)-4-(isopropylamino)quinazolin-7-ol
##STR00128##
[0784] Acetate salt of the compound 3.5.a.1 (1.05 g, 3.13 mmol) is
presented as an initial charge in 60 mL of tetrahydrofuran and at
0.degree. C. admixed portionwise with lithium aluminium hydride
(590 mg, 15.7 mmol). This is followed by stirring at room
temperature for 90 minutes. The reaction is discontinued by
addition of 10% aqueous ammonium chloride solution at 0.degree. C.
The batch is diluted with water and extracted with ethyl acetate,
and the combined organic phases are dried over sodium sulphate to
leave, after removal of the solvent, the desired product in 70%
yield (510 mg).
[0785] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.24 (d, 6H),
4.47-4.54 (m, 1H), 4.59 (s, 2H), 5.15 (br, 1H), 6.92 (s, 1H), 7.74
(d, 1H), 8.19 (s, 1H), 8.28 (s, 1H), 10.30 (br, 1H).
Compound 2.11.a.2
7-Hydroxy-4-(isopropylamino)quinazoline-6-carbaldehyde
##STR00129##
[0787] 6-(Hydroxymethyl)-4-(isopropylamino)quinazoline-7-ol (510
mg, 2.19 mmol) is dissolved in 50 mL of toluene and 5 mL of
dimethylformamide and at room temperature admixed portionwise with
manganese(IV) oxide (1.9 g, 21.9 mmol). After 24 hours the batch is
filtered through Celite and washed with dichloro-methane/methanol
9/1. Removal of the solvent and also chromatographic purification
(silica gel, dichloromethane/methanol: 0.fwdarw.50% methanol) gives
the desired product in 56% yield (280 mg).
[0788] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.20 (d, 6H),
4.41-4.52 (m, 1H), 6.97 (s, 1H), 8.29-8.32 (m, 2H), 8.72 (s, 1H),
10.30 (s, 1H), 11.22 (br, 1H).
Compound 2.11.a.3
7-Hydroxy-4-(isopropylamino)quinazoline-6-carbonitrile
##STR00130##
[0790] 7-Hydroxy-4-(isopropylamino)quinazoline-6-carbaldehyde (310
mg, 1.34 mmol) is presented as an initial charge in acetic acid (7
mL, 81 mmol) and admixed with sodium acetate (366 mg, 3.3 mmol) and
also hydroxylamine hydrochloride (186 mg, 2.68 mmol). The batch is
stirred at 130.degree. C. for 18 hours. After cooling to room
temperature, the batch is diluted with water and extracted with
ethyl acetate. The combined organic phases are dried over sodium
sulphate. Removal of the solvent and also chromatographic
purification (silica gel, dichloromethane/methanol: 0.fwdarw.30%
methanol) of the residue gives the desired product in 38% yield
(116 mg).
[0791] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.20 (d, 6H),
4.38-4.46 (m, 1H), 6.94 (s, 1H), 8.06 (d, 1H),8.35 (s, 1H), 8.74
(s, 1H), 11.87 (br, 1H).
[0792] 2.11.b) Preparation of the Final Product
[0793] 7-Hydroxy-4-(isopropylamino)quinazoline-6-carbonitrile (50
mg, 0.22 mmol) and
(RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulph-
oximide (105 mg, 0.33 mmol) are suspended in 5.0 mL of acetone.
After addition of potassium carbonate (56 mg, 0.4 mmol), the
reaction mixture is refluxed for 6 hours. The batch is diluted with
ethyl acetate and the organic phase is washed with water and dried
over sodium sulphate. Removal of the solvent and also
chromatographic purification (silica gel, dichloromethane/methanol:
0.fwdarw.30% methanol) gives the desired product in 74% yield (75
mg).
[0794] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.01 (t, 3H),
1.21 (d, 6H), 3.44 (s, 3H), 3.80-3.89 (m, 2H), 4.38-4.47 (m, 1H),
5.50 (s, 2H), 7.33 (s, 1H), 7.73 (t, 1H), 7.86 (d, 1H), 7.93 (d,
1H), 8.08 (s, 1H), 8.12 (d, 1H), 8.44 (s, 1H), 8.88 (s, 1H).
EXAMPLE 2.12
(RS)-S-{[3-(1[6-Cyano-4-(isopropylamino)quinazolin-7-yl]oxy}methyl)phenyl]-
-S-methylsulphoximide
##STR00131##
[0796] According to GWP 6, the conversion of
(RS)-S-[3-({[6-cyano-4-(isopropylamino)-quinazolin-7-yl]oxy}methyl)phenyl-
]-N-(ethoxycarbonyl)-S-methylsulphoximide (65 mg, 0.14 mmol) and
chromatographic purification (silica gel, dichloromethane/methanol:
0.fwdarw.30% methanol) gives the desired product in 74% yield (41
mg).
[0797] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.21 (d, 6H),
3.04 (s, 3H), 4.24 (s, 1H), 4.37-4.49 (m, 1H), 5.47 (s, 2H), 7.32
(s, 1H), 7.65 (t, 1H), 7.75 (d, 1H), 7.90 (d, 1H), 8.06 (s, 1H),
8.12 (d, 1H), 8.44 (s, 1H), 8.87 (s, 1H).
[0798] 3. Process Variant 3
EXAMPLE 3.1
(RS)-S-(4-{[4-(Isopropylamino)-6-methoxyquinazolin-7-yl]oxy}butyl)-S-methy-
l-N-[(4-nitrophenyl)sulphonyl]sulphoximide
##STR00132##
[0800] 3.1.a) Preparation of the Intermediates
Compound 3.1.a.1
Isopropyl-[6-methoxy-7-(4-methylsulphanylbutoxy)quinazolin-4-yl]amine
##STR00133##
[0802] 4-(Isopropylamino)-6-methoxyquinazolin-7-ol (380 mg, 1.63
mmol) is dissolved in methylene chloride (10 ml) under an argon
atmosphere, treated with triphenylphosphine (641 mg, 2.44 mmol),
azodicarboxylic acid dipiperidide (617 mg, 2.44 mmol) and
4-(methylthio)butan-1-ol (235 mg, 1.96 mmol) and stirred at room
temperature for 20 hours. The batch is diluted with methylene
chloride and water, and the organic phase is separated off and
concentrated. The desired product is obtained after chromatography
by means of preparative HPLC in 43% yield (258 mg).
[0803] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.27 (d, 6H),
1.67-1.77 (m, 2H), 1.82-1.90 (m, 2H), 2.05 (s, 3H), 2.56 (t, 2H),
3.90 (s, 3H), 4.11 (t, 2H), 4.49 (dsept, 1H), 7.06 (s, 1H), 7.52
(d, 1H), 7.60 (s, 1H), 8.31 (s, 1H).
Compound 3.1.a.2
(RS)-S-(4-{[4-(Isopropylamino)-6-methoxyquinazolin-7-yl]oxy}butyl)-S-methy-
l-N-[(4-nitrophenyl)sulphonyl]sulphimide
##STR00134##
[0805] According to Bolm et al. (Org. Lett 2006, 8(11), 2349-2352),
isopropyl-[6-methoxy-7-(4-methylsulphanylbutoxy)quinazolin-4-yl]amine
(250 mg, 075 mmol) is dissolved in acetonitrile (7 ml) under an
argon atmosphere, treated with
N-(p-nitrosulphonyl-phenyl)imino)phenyliodinane (452 mg, 1.12 mmol)
and iron(III) acetylacetonate (14 mg, 0.04 mmol) and stirred at
room temperature for 20 hours. The desired product is obtained
after removal of the solvent and chromatographic purification
(silica gel, dichloromethane/methanol: 25/1) in 67% yield (272
mg).
[0806] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.28 (d, 6H),
1.60-1.80 (m, 4H), 2.71 (s, 3H), 3.08-3.22 (m, 2H), 3.90 (s, 3H),
3.99-4.04 (m, 2H), 4.46-4.55 (m, 1H), 7.03 (s, 1H), 7.59 (br s,
1H), 7.62 (s, 1H), 7.98 (d, 2H), 8.30 (d, 2H), 8.34 (s, 1H).
[0807] 3.1.b) Preparation of the Final Product
[0808]
(RS)-S-(4-{[4-(Isopropylamino)-6-methoxyquinazolin-7-yl]oxy}butyl)
-S-methyl-N-[(4-nitrophenyl)sulphonyl]sulphimide (268 mg, 0.5 mmol)
is suspended in acetonitrile (0.6 ml) and ethanol (8 ml), treated
with potassium carbonate (156 g, 1.13 mmol) and a solution of
ethanol (8 ml) and hydrogen peroxide (0.6 ml) and stirred at room
temperature for 20 hours. The reaction batch is diluted with water.
After removing ethanol and acetonitrile, the aqueous phase is
extracted with methylene chloride and small amounts of methanol as
a solubilizer. The organic phase is dried over sodium sulphate.
After removal of the solvent, the residue is dissolved in a little
methylene chloride, treated with diethyl ether, triturated and
concentrated again. The desired product is obtained in 88% yield
(267 mg).
[0809] LC-MS (method: see Compound 1.16.a.3):R.sub.t=1.34 min; MS
(ESI pos.): m/z=552 (M+H.sup.+).
EXAMPLE 3.2
(RS)-S-(4-{[4-(Isopropylamino)-6-methoxyquinazolin-7-yl]oxy}butyl)-S-methy-
l-sulphoximide
##STR00135##
[0811]
(RS)-S-(4-{[4-(Isopropylamino)-6-methoxyquinazolin-7-yl]oxy}butyl)--
S-methyl-N-[(4-nitrophenyl)sulphonyl]sulphoximide (267 mg, 0.48
mmol) is dissolved in acetonitrile (7 ml), treated with caesium
carbonate (266 mg, 0.82 mmol) and thiophenol (86 mg, 0.77 mmol) and
stirred at room temperature for 20 hours. The reaction batch is
diluted with water and methylene chloride. The organic phase is
separated off and dried over sodium sulphate. The desired product
is obtained after removal of the solvent and preparative HPLC in
51% yield (126 mg).
[0812] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.27 (d, 6H),
1.83-1.95 (m, 4H), 2.89 (s, 3H), 3.12-3.18 (m, 2H), 3.61 (s, 1H),
3.91 (s, 3H), 4.10-4.15 (m, 2H), 4.49 (dsept, 1H), 7.08 (s, 1H),
7.53 (d, 1H), 7.61 (s, 1H), 8.31 (s, 1H).
EXAMPLE 3.3
(RS)-S-(4-{[4-(Isopropylamino)-6-methoxyquinazolin-7-yl]oxy}propyl)-S-meth-
yl-N-[(4-nitrophenyl)sulphonyl]sulphoximide
##STR00136##
[0814] 3.3.a) Preparation of the Intermediates
Compound 3.3.a.1
Isopropyl-[6-methoxy-7-(4-methylsulphanylpropoxy)quinazolin-4-yl]amine
##STR00137##
[0816] 4-(Isopropylamino)-6-methoxyquinazolin-7-ol (400 mg, 1.72
mmol) is dissolved in methylene chloride (10 ml) under an argon
atmosphere, treated with triphenylphosphine (675 mg, 2.57 mmol),
azodicarboxylic acid dipiperidide (649 mg, 2.57 mmol) and
3-(methylthio)propan-1-ol (219 mg, 2.06 mmol) and stirred at room
temperature for 20 hours. The batch is diluted with methylene
chloride and water, and the organic phase is separated off and
concentrated. The desired product is obtained after preparative
HPLC in 35% yield (190 mg).
[0817] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.27 (d, 6H), 2.04
(tt, 2H), 2.08 (s, 3H), 2.64 (t, 2H), 3.91 (s, 3H), 4.17 (t, 2H),
4.49 (dsept, 1H), 7.07 (s, 1H), 7.53 (d, 1H), 7.61 (s, 1H), 8.32
(s, 1H).
Compound 3.3.a.2
(RS)-S-(4-{[4-(Isopropylamino)-6-methoxyquinazolin-7-yl]oxy}propyl)-S-meth-
yl-N-[(4-nitrophenyl)sulphonyl]sulphimide
##STR00138##
[0819]
Isopropyl-[6-methoxy-7-(4-methylsulphanylpropoxy)quinazolin-4-yl]am-
ine (95 mg, 0.296 mmol) is dissolved in acetonitrile (2 ml) under
an argon atmosphere, treated with iodosylbenzene (104 mg, 0.47
mmol), 4-nitrobenzenesulphonamide (90 mg, 0.44 mmol) and iron(III)
acetylacetonate (5.2 mg, 0.015 mmol) and stirred at room
temperature for 2 hours. The desired product is obtained after
removal of the solvent and chromatographic purification (silica
gel, ethyl acetate then dichloromethane/methanol: 10/1), in 31%
yield (48 mg).
[0820] LC-MS (Instrument: Micromass Quattro LCZ with HPLC Agilent
Series 1100; column: Phenomenex Onyx Monolithic C18, 100 mm.times.3
mm. eluent A: 1 l of water+0.5 ml of 50% strength formic acid,
eluent B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid;
gradient: 0.0 min 90% A.fwdarw.2 min 65% A.fwdarw.4.5 min 5%
A.fwdarw.6 min 5% A; flow: 2 ml/min; oven: 40.degree. C.; UV
detection: 208-400 nm):R.sub.t=1.99 min; MS (ESI pos.): m/z=522
(M+H.sup.+).
[0821] 3.3.b) Preparation of the Final Product
[0822]
(RS)-S-(4-{[4-(lsopropylamino)-6-methoxyquinazolin-7-yl]oxy}propyl)
-S-methyl-N-[(4-nitrophenyl)sulphonyl]sulphimide (45 mg, 0.086
mmol) and potassium carbonate (25 mg, 0.18 mmol) are dissolved in
N,N-dimethylformamide (1 ml) and treated at 0.degree. C. with
meta-chloroperbenzoic acid (26 mg, 0.104 mmol). After 2 hours at
room temperature, the batch is added to water, extracted with ethyl
acetate and the combined organic phases are dried over sodium
sulphate. The desired product is obtained after removal of the
solvent and subsequent purification (silica gel,
dichloromethane/methanol: 100/3) with 47% yield (22 mg).
[0823] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.27 (d, 6H),
2.24-2.34 (m, 2H), 3.59 (s, 3H), 3.72-3.90 (m, 2H), 3.91 (s, 3H),
4.22 (t, 2H), 4.45-4.54 (m, 1H), 7.06 (s, 1H), 7.56 (d, 1H), 7.63
(s, 1H), 8.10 (d, 2H), 8.32 (s, 1H), 8.36 (d, 2H).
EXAMPLE 3.4
(RS)-S-(4-{[4-(Isopropylamino)-6-methoxyquinazolin-7-yl]oxy}propyl)-S-meth-
yl-sulphoximide
##STR00139##
[0825] For the removal of the protective group on the sulphoximine,
a 3-(4-tritylmercapto)-phenylpropionyl AM resin is used, which is
prepared for the reaction in the following way (based on 89 mg,
0.078 mmol of resin): a) The resin is suspended 1/1 in 2 ml of
methylene chloride/trifluoroacetic acid, shaken for 5 minutes and
the solution is separated off. This process is repeated five times
until the solution is colourless. The resin is in each case washed
with methylene chloride and tetrahydrofuran. b) The resin is
subsequently taken up in 2 ml of tetrahydrofuran/methanol 9/1 and
treated with sodium ethoxide in methanol (5.4 M solution, 29
.mu.l), and shaken for 5 minutes. The reaction solution is
separated off and the resin is washed with tetrahydrofuran.
(RS)-S-(4-{[4-(Isopropylamino)-6-methoxyquinazolin-7-yl]oxy}propyl)-S-met-
hyl-N-[(4-nitrophenyl)sulphonyl]sulphoximide (21 mg, 0.039 mmol) is
introduced into ethanol (1.5 ml) and treated with the prepared
resin (455 mg, 0.39 mmol) and shaken overnight. The resin is
filtered off and washed with tetrahydrofuran. The desired product
is obtained after removing the solvents and chromatographic
purification (silica gel, dichloromethane/methanol: 5/1) in 42%
yield (5.8 mg).
[0826] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.27 (d, 6H),
2.18-2.27 (m, 2H), 2.94 (s, 3H), 3.21 (t, 2H), 3.79 (br s, 1H),
3.91 (s, 3H), 4.22 (t, 2H), 4.49 (dsept, 1H), 7.08 (s, 1H), 7.56
(d, 1H), 7.63 (s,1H), 8.32 (s,1H).
EXAMPLE 3.5
Ethyl
4-(isopropylamino)-7-[(RS)-3-{S-methyl-N-[(4-nitrophenyl)sulphonyl]--
sulphonimidoyl}propoxy]quinazoline-6-carboxylate
##STR00140##
[0828] 3.5.a) Preparation of the Intermediates
Compound 3.5.a.1
Ethyl 7-hydroxy-4-(isopropylamino)quinazoline-6-carboxylate
##STR00141##
[0830] According to GWP 5, ethyl
5-cyano-4-{(E/Z)-[(dimethylamino)methylene]amino}-2-hydroxybenzoate
(1.9 g, 7.27 mmol) is reacted with isopropylamine (516 mg, 8.73
mmol) in acetonitrile (10 ml) and acetic acid (5 ml). After
cooling, the batch is diluted with water, rendered alkaline with
concentrated sodium hydroxide solution, and extracted with ethyl
acetate and methanol as a solubilizer. The organic phase is dried
over sodium sulphate. After removal of the solvent, the residue is
triturated a number of times with methylene chloride and employed
in the next reaction without further purification. The desired
product is obtained in 66% yield (1.6g)
[0831] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.26 (d, 6H), 1.39
(t, 3H), 1.91 (s, 3H), 4.43 (q, 2H), 4.52 (dsept, 1H), 7.01 (s,
1H), 8.25 (d, 1H), 8.37 (s, 1H), 8.81 (s, 1H), 10.82 (br s, 1H),
11.97 (br s, 1H).
Compound 3.5.a.2
Ethyl
4-(isopropylamino)-7-[3-(methylsulphanyl)propoxy]quinazoline-6-carbo-
xylate
##STR00142##
[0833] Sodium hydride (60%, 251 mg, 6.3 mmol) is introduced into
N,N-dimethylformamide (13 ml), treated in portions with ethyl
7-hydroxy-4-(isopropylamino)quinazoline-6-carboxylate (1 g, 2.98
mmol) and subsequently stirred at room temperature for 30 minutes.
After addition of a solution of 3-(methylthio)-1-(tosyloxy)propane
(777 mg, 2.98 mmol) in N,N-dimethylformamide (8 ml), the mixture is
stirred at 80.degree. C. for one hour. After cooling, the batch is
treated with water and ethyl acetate, and the organic phase is
separated off and dried over sodium sulphate. The desired product
is obtained after removing the solvents and preparative HPLC in 48%
yield (548 mg).
[0834] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.25 (d, 6H), 1.34
(t, 3H), 2.02 (quint, 2H), 2.07 (s, 3H), 2.68 (t, 2H), 4.21 (t,
2H), 4.33 (q, 2H), 4.50 (dsept, 1H), 7.13 (s, 1H), 8.12 (d, 1H),
8.42 (s, 1H), 8.64 (s, 1H).
Compound 3.5.a.3
Ethyl
4-(isopropylamino)-7-[(RS)-3-{S-methyl-N-[(4-nitrophenyl)sulphonyl]--
sulphinimidoyl}propoxy]quinazoline-6-carboxylate
##STR00143##
[0836] Ethyl
4-(isopropylamino)-7-[3-(methylsulphanyl)propoxy]quinazoline-6-carboxylat-
e (237 mg, 0.65 mmol) is dissolved in acetonitrile (6 ml) under an
argon atmosphere, treated with
(N-(p-nitrosulphonylphenyl)imino)phenyliodinane (396 mg, 0.98 mmol)
and iron(II) acetylacetonate (12 mg, 0.033 mmol) and stirred at
room temperature for 20 hours. The desired product is obtained
after removal of the solvent and chromatographic purification
(silica gel, dichloromethane/methanol: 25/1), in 91% yield (347
mg).
[0837] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.26 (d, 6H), 1.33
(t, 3H), 1.93-2.14 (m, 2H), 2.76 (s, 3H), 3.15-3.28 (m, 2H), 4.13
(t, 2H), 4.32 (q, 2H), 4.50 (dsept, 1H), 7.06 (s, 1H), 7.97 (d,
2H), 8.16 (d, 1H), 8.28 (d, 2H), 8.43 (s, 1H), 8.65 (s, 1H).
[0838] 3.5.b) Preparation of the Final Product
[0839] Ethyl
4-(isopropylamino)-7-[(RS)-3-{S-methyl-N-[(4-nitrophenyl)sulphonyl]-sulph-
inimidoyl}propoxy]quinazoline-6-carboxylate (340 mg, 0.6 mmol) is
suspended in acetonitrile (0.7 ml) and ethanol (10 ml), treated
with potassium carbonate (188 g, 1.36 mmol) and a solution of
ethanol (8 ml) and hydrogen peroxide (0.66 ml) and stirred at room
temperature for 20 hours. The reaction batch is diluted with water.
After removing ethanol and acetonitrile, the aqueous phase is
extracted with methylene chloride. The organic phase is dried over
sodium sulphate. After removal of the solvent, the residue is
dissolved in a little methylene chloride, treated with diethyl
ether, triturated and concentrated again. The desired product is
obtained in 72% yield (271 mg).
[0840] LC-MS (apparatus type MS: Waters ZQ; apparatus type HPLC:
Waters alliance 2795; column: Phenomenex Onyx Monolithic C18, 100
mm.times.3 mm; eluent A: 1 l of water+0.5 ml of 50% strength formic
acid, eluent B: 1 l of acetonitrile+0.5 ml of 50% strength formic
acid; gradient: 0.0 min 90% A.fwdarw.2 min 65% A.fwdarw.4.5 min 5%
A.fwdarw.6 min 5% A; flow: 2 ml/min; oven: 40.degree. C.; UV
detection: 210 nm):R.sub.t=2.58 min; MS (ESI pos.): m/z=580
(M+H.sup.+).
EXAMPLE 3.6
Ethyl
4-(isopropylamino)-7-[(RS)-3-(S-methylsulphonimidoyl)propoxy]-quinaz-
oline-6-carboxylate
##STR00144##
[0842] Ethyl 4-(isopropylamino)-7-[(RS)-3-{S-methyl
-N-[(4-nitrophenyl)sulphonyl]-sulphonimidoyl}propoxy]quinazoline-6-carbox-
ylate (270 mg, 0.47 mmol) is dissolved in acetonitrile (7 ml),
treated with caesium carbonate (276 mg, 0.85 mmol) and thiophenol
(90 mg, 0.82 mmol) and stirred at room temperature for 20 hours.
The reaction batch is diluted with water and methylene chloride.
The organic phase is separated off and dried over sodium sulphate.
The desired product is obtained after removal of the solvent,
preparative HPLC and subsequent repeated trituration of the residue
in 45% yield (83 mg).
[0843] .sup.1H-NMR (400 MHz, DMSO-d6): .delta. 1.25 (d, 6H), 1.35
(t, 3H), 2.17-2.25 (m, 2H), 2.93 (s, 3H), 3.22-3.27 (m, 2H), 3.75
(s, 1H), 4.27 (t, 2H), 4.35 (q, 2H), 4.50 (dsept, 1H), 7.14 (s,
1H), 8.14 (d, 1H), 8.42 (s, 1H), 8.66 (s, 1H).
EXAMPLE 3.7
(RS)-S-[5-({[6-Bromo-4-(isopropylamino)quinazolin-7-yl]oxy}methyl)pyridin--
3-yl]-S-methylsulphoximide
##STR00145##
[0845] 3.7.a) Preparation of the Intermediates
Compound 3.7.a.1
5-(Methylsulphanyl)pyridine-3-methanol
##STR00146##
[0847] Methyl 5-methylsulphanylnicotinate (916 mg, 5 mmol) is
dissolved in 150 mL of diethyl ether, admixed at 0.degree. C. with
lithium aluminium hydride (660 mg, 18 mmol) and subsequently
stirred at room temperature for 90 minutes. The reaction is
discontinued by addition of 10% ammonium chloride solution at
0.degree. C. The batch is diluted with water and the aqueous phase
is extracted with ether. Drying of the organic phase over sodium
sulphate, concentrating the solvent and also chromatographic
purification of the residue (silica gel, n-hexane/ethyl acetate:
50.fwdarw.100% ethyl acetate) gives the desired product in 7% yield
(50 mg).
[0848] .sup.1H-NMR (300 MHz, DMSO): .differential. 2.53 (s, 3H),
4.52 (s, 2H), 5.36 (br, 1H), 7.63 (t, 1H), 8.30 (d, 1H), 8.35 (d,
1H).
Compound 3.7.a.2
N'-(4-Bromo-2-cyano-5-{[5-(methylsulphanyl)pyridin-3-yl]methoxy}phenyl)-N,-
N-dimethylformimidamide
##STR00147##
[0850]
(E/Z)-N'-(4-Bromo-2-cyano-5-hydroxyphenyl)-N,N-dimethylformimidamid-
e (242 mg, 0.9 mmol) is dissolved in 30 mL of tetrahydrofuran,
admixed with 5-(methyl-sulphanyl)pyridine-3-methanol (280 mg, 1.8
mmol), triphenylphosphine (1.42 g, 5.41 mmol) and DEAD (943 mg,
5.41 mmol) and stirred at RT for 4 h. The reaction mixture is
diluted with ethyl acetate and the organic phase is washed with
saturated sodium bicarbonate solution. Drying of the organic phase
over sodium sulphate, concentrating of the solvent and also
chromatographic purification of the residue (silica gel, n-hexane,
followed by ethyl acetate) gives the desired product in 11% yield
(78 mg).
[0851] .sup.1H-NMR (300 MHz, DMSO): .differential. 2.51 (s, 3H),
2.97 (s, 3H), 3.07 (s, 3H), 5.26 (s, 2H), 6.97 (s, 1H), 7.78 (t,
1H), 7.80 (s, 1H), 7.99 (s, 1H), 8.42 (d, 1H), 8.44 (d, 1H).
Compound 3.7.a.3
6-Bromo-N-isopropyl-7-{[5-(methylsulphanyl)pyridin-3-yl]methoxy}quinazolin-
-4-amine
##STR00148##
[0853] According to GWP 5, the reaction of
N'-(4-bromo-2-cyano-5-{[5-(methylsulphanyl)-pyridin-3-yl]methoxy}phenyl)--
N,N-dimethylformimidamide (540 mg, 1.33 mmol) with isopropylamine
(0.14 mL, 1.6 mmol) and chromatography (silica gel,
dichloro-methane/methanol: 0.fwdarw.30% methanol) gives the desired
product in 77% yield (430 mg)
[0854] .sup.1H-NMR (400 MHz, DMSO): .differential. 1.21 (d, 6H),
2.52 (s, 3H), 4.40-4.45 (m,1H), 5.35 (s, 2H), 7.28 (s, 1H), 7.81
(t, 1H), 7.89 (d, 1H), 8.39 (s, 1H), 8.43 (d, 1H), 8.46 (d, 1H),
8.66 (s, 1H).
Compound 3.7.a.4
6-Bromo-N-isopropyl-7-{[5-(methylsulphinyl)pyridin-3-yl]methoxy}quinazolin-
-4-amine
##STR00149##
[0856]
6-Bromo-N-isopropyl-7-{[5-(methylsulphanyl)pyridin-3-yl]methoxy}qui-
nazolin-4-amine (430 mg, 1.03 mmol) is presented as an initial
charge in 20 mL of chloroform and at 0.degree. C. and at 0.degree.
C. admixed with meta-chloroperbenzoic acid (260 mg, 1.13 mmol). The
batch is subsequently stirred at 0.degree. C. for 45 minutes. The
batch is introduced into 2N aqueous sodium hydroxide solution. The
mixture is extracted with dichloro-methane, the organic phase is
dried over sodium sulphate and the solvent is concentrated.
Chromatography (silica gel, dichloromethane/methanol: 0.fwdarw.30%
methanol) gives the desired product in 74% yield (330 mg).
[0857] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.21 (d, 6H),
2.84 (s, 3H), 4.39-4.46 (m, 1H), 5.47 (s, 2H), 7.31 (s, 1H), 7.90
(d, 1H), 8.25 (t, 1H), 8.39 (s, 1H), 8.67 (s, 1H), 8.81 (d, 1H),
8.85 (d, 1H).
[0858] 3.7.b) Preparation of the End Product
[0859] According to GWP
2,6-bromo-N-isopropyl-7-{[5-(methylsulphinyl)pyridin-3-yl]-methoxy}quinaz-
olin-4-amine (270 mg, 0.62 mmol) is suspended in chloroform (10 mL)
and admixed with sodium azide (90 mg, 1.39 mmol). Sulphuric acid
(0.32 mL, 5.92 mmol) is added dropwise at 0.degree. C. The reaction
mixture is subsequently stirred at 45.degree. C. for 24 hours.
After cooling to room temperature, the batch is neutralized with 4N
aqueous sodium hydroxide solution, concentrated under reduced
pressure and evaporated off with toluene in a rotary evaporator.
After purification of the residue by means of HPLC (column: XBridge
C18 5.mu. 150.times.30 mm, eluent A: H.sub.2O/0.2% NH.sub.3, eluent
B: methanol, gradient: 0.0 min 50% A.fwdarw.11 min 20%
A.fwdarw.14.98 min 1% A, flow rate: 50 mL/min, room temperature,
detection: DAD (200-400 nm) TAC; MS-ESI+ (m/z=160-1000 m/z) TIC,
Rt: 4.5-5.2 min) the desired product is obtained in 21% yield (57
mg).
[0860] .sup.1H-NMR (300 MHz, DMSO): .differential. 1.25 (d, 6H),
3.19 (s, 3H), 4.47 (m, 1H), 5.53 (s, 2H), 7.36 (s, 1H), 7.96 (br,
1H), 8.44-8.49 (m, 2H), 8.73 (s, 1H), 8.99 (d, 1H), 9.07 (d,
1H).
II. BIOLOGICAL ACTIONS OF THE COMPOUNDS ACCORDING TO THE
INVENTION
[0861] TLR-Induced Cytokine Release in Human "Peripheral Blood
Mononuclear Cells" (PBMC)
[0862] Test Principle
[0863] PBMCs isolated from human whole blood are stimulated using a
TLR ligand. The cytokine determination is carried out by means of
ELISA kits; a proliferation/cell metabolism determination is
carried out using Alamar Blue.
[0864] PBMC Isolation:
[0865] For the cell preparation, about 200 ml of blood are treated
with an anticoagulant (e.g. citrate Monovettes). Per Leucosep tube,
15 ml of Histopaque (room temperature, RT) are poured in and
pressed downwards through the frit employed by brief initial
centrifugation (one minute at 1000.times.g, RT). 20 ml of blood are
added to the tubes prepared in this way and centrifuged at
800.times.g for 15 minutes (RT). After centrifugation, the
following layered arrangement results from the top to the bottom:
plasma--PBMC--Histopaque--filter disc--Histopaque--erythrocytes and
granulocytes. The supernatant plasma is aspirated. The PBMC are
transferred together with the underlying Histopaque to a new 50 ml
tube, the contents of two Leucosep tubes always being added to one
50 ml tube. The 50 ml tubes are then filled to 50 ml with PBS. This
cell suspension is centrifuged at 300.times.g (RT) for 10 minutes.
The liquid supernatant is tipped off and the cell pellet is
resuspended with a little PBS and subsequently filled to 50 ml with
PBS. This washing step is repeated twice. The resulting pellet is
taken up in a defined volume of medium (with additives). For the
testing of the substances, PBMC are incubated for 18 hours with
titrated concentrations of the test substances, e.g. in the
presence or absence of TLR ligands. On the next day, the
supernatants are investigated for the content of IL-12, TNF-alpha
or other chemokines by means of specific ELISA. The metabolic
activity of the treated cells is determined with the aid of Alamar
Blue.
[0866] Results:
TABLE-US-00001 Example IC.sub.50 (TNF-.alpha.) IC.sub.50 (IL-12)
1.2 2.1 .mu.M 4.1 .mu.M 2.8 4 .mu.M 15 .mu.M 2.10 0.2 .mu.M 0.4
.mu.M 3.4 10 .mu.M 15 .mu.M 3.7 1 .mu.M 4 .mu.M
[0867] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The preceding preferred
specific embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
[0868] In the foregoing and in the examples, all temperatures are
set forth uncorrected in degrees Celsius and, all parts and
percentages are by weight, unless otherwise indicated.
[0869] The entire disclosures of all applications, patents and
publications, cited herein and of corresponding European
application No. 08075043.3, filed Jan. 17, 2008, and U.S.
Provisional Application Ser. No. 61/039,621, filed Mar. 26, 2008,
are incorporated by reference herein.
[0870] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0871] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *